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Ma L, Fink J, Yao K, McDonald-Hyman C, Dougherty P, Koehn B, Blazar BR. Immunoregulatory iPSC-derived non-lymphoid progeny in autoimmunity and GVHD alloimmunity. Stem Cells 2025; 43:sxaf011. [PMID: 40103180 DOI: 10.1093/stmcls/sxaf011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/19/2025] [Indexed: 03/20/2025]
Abstract
Non-lymphoid immunoregulatory cells, including mesenchymal stem cells (MSCs), myeloid-derived suppressor cells (MDSCs), regulatory macrophages (Mregs), and tolerogenic dendritic cells (Tol-DCs), play critical roles in maintaining immune homeostasis. However, their therapeutic application in autoimmune diseases and graft-versus-host disease (GVHD) has received comparatively less attention. Induced pluripotent stem cells (iPSCs) offer a promising platform for cell engineering, enabling superior quality control, scalable production, and large-scale in vitro expansion of iPSC-derived non-lymphoid immunoregulatory cells. These advances pave the way for their broader application in autoimmune disease and GVHD therapy. Recent innovations in iPSC differentiation protocols have facilitated the generation of these cell types with functional characteristics akin to their primary counterparts. This review explores the unique features and generation processes of iPSC-derived non-lymphoid immunoregulatory cells, their therapeutic potential in GVHD and autoimmune disease, and their progress toward clinical translation. It emphasizes the phenotypic and functional diversity within each cell type and their distinct effects on disease modulation. Despite these advancements, challenges persist in optimizing differentiation efficiency, ensuring functional stability, and bridging the gap to clinical application. By synthesizing current methodologies, preclinical findings, and translational efforts, this review underscores the transformative potential of iPSC-derived non-lymphoid immunoregulatory cells in advancing cell-based therapies for alloimmune and autoimmune diseases.
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Affiliation(s)
- Lie Ma
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Jordan Fink
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Ke Yao
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Cameron McDonald-Hyman
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, United States
| | - Phillip Dougherty
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Brent Koehn
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN, United States
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Withers HG, Matsuzaki J, Long M, Rosario SR, Chodon T, Tsuji T, Koya R, Yan L, Wang J, Keler T, Lele SB, Zsiros E, Lugade A, Hutson A, Blank S, Bhardwaj N, Shrikant P, Liu S, Odunsi K. mTOR inhibition modulates vaccine-induced immune responses to generate memory T cells in patients with solid tumors. J Immunother Cancer 2025; 13:e010408. [PMID: 40132910 PMCID: PMC11956311 DOI: 10.1136/jitc-2024-010408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 03/06/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Perturbation of the mechanistic target of rapamycin (mTOR) pathway can instruct effector versus memory cell fate of tumor antigen-specific T cells in preclinical models. In this study, we sought to understand the impact of rapamycin (sirolimus), an mTOR inhibitor, on reprogramming vaccine-induced T cells to enhance memory responses in patients with solid tumors following completion of their standard therapy. METHODS We conducted three phase I clinical trials employing New York esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccination approaches, with or without schedule-varied rapamycin. T cell phenotypes, functions, and Vβ usage in peripheral blood were analyzed to ask whether rapamycin influenced the generation of vaccine-induced T cells with memory attributes. RESULTS The addition of rapamycin to all vaccination approaches was safe and well tolerated. Immediate (days 1-14 postvaccination) or delayed (days 15-28 postvaccination) administration of rapamycin led to a significant increase in the generation of vaccine-induced NY-ESO-1-specific T cells exhibiting central memory phenotypes (CD45RO+CD45RA- CCR7+). Moreover, delayed administration resulted in a greater than threefold (p=0.025) and eightfold (p=0.005) increase in the frequency of NY-ESO-1-specific CD4+ T and CD8+ T cells respectively at the time of long-term follow-up, compared with its immediate usage. CONCLUSION Our novel finding is that delayed administration of rapamycin to patients during the contraction phase of vaccine-induced antitumor immune responses was particularly effective in increasing the frequency of memory T cells up to 1 year postvaccination in patients with solid tumors. Further studies are warranted to identify the impact of this approach on the durability of clinical remission. TRIAL REGISTRATION NUMBER NCT00803569, NCT01536054, NCT01522820.
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Affiliation(s)
- Henry G Withers
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Junko Matsuzaki
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA
- UChicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
| | - Mark Long
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Spencer R Rosario
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Thinle Chodon
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA
- UChicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
| | - Takemasa Tsuji
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA
- UChicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
| | - Richard Koya
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA
- UChicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Jianming Wang
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Tibor Keler
- R&D, Celldex Therapeutics, Hampton, New Jersey, USA
| | - Shashikant B Lele
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Emese Zsiros
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Amit Lugade
- Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Alan Hutson
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Stephanie Blank
- Department of Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai Tisch Cancer Institute, New York, New York, USA
| | - Nina Bhardwaj
- Icahn School of Medicine at Mount Sinai Tisch Cancer Institute, New York, New York, USA
| | - Protul Shrikant
- Department of Immunobiology, The University of Arizona College of Medicine Tucson, Tucson, Arizona, USA
| | - Song Liu
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Kunle Odunsi
- Department of Obstetrics and Gynecology, The University of Chicago, Chicago, Illinois, USA
- UChicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA
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Gabrielli F, Bernasconi E, Toscano A, Avossa A, Cavicchioli A, Andreone P, Gitto S. Side Effects of Immunosuppressant Drugs After Liver Transplant. Pharmaceuticals (Basel) 2025; 18:342. [PMID: 40143120 PMCID: PMC11946649 DOI: 10.3390/ph18030342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 02/18/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Liver transplantation (LT) is the standard of care for both end-stage liver failure and hepatocellular carcinoma (HCC). Side effects of the main used immunosuppressive drugs have a noteworthy impact on the long-term outcome of LT recipients. Consequently, to achieve a balance between optimal immunosuppression and minimal side effects is a cornerstone of the post-LT period. Today, there are no validated markers for overimmunosuppression and underimmunosuppression, only a few drugs have therapeutic drug monitoring, and immunosuppression regimens vary from center to center and from country to country. Currently, there are many drugs with different efficacy and safety profiles. Using different agents permits a decrease in the dosage and minimizes the toxicities. A small subset of recipients achieves immunotolerance with the chance to stop immunosuppressive therapy. This article focuses on the side effects of immunosuppressive drugs, which significantly impact long-term outcomes for LT recipients. The primary aim is to highlight the balance between achieving effective immunosuppression and minimizing adverse effects, emphasizing the role of personalized therapeutic strategies. Moreover, this review evaluates the mechanisms of action and specific complications associated with immunosuppressive agents. Finally, special attention is given to strategies for reducing immunosuppressive burdens, improving patient quality of life, and identifying immunotolerant individuals.
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Affiliation(s)
- Filippo Gabrielli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Elisa Bernasconi
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Arianna Toscano
- Division of Internal Medicine, University Hospital of Policlinico G. Martino, 98124 Messina, Italy
| | - Alessandra Avossa
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Alessia Cavicchioli
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences for Children & Adults, AOU of Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
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Stiepel RT, Simpson SR, Lukesh NR, Middleton DD, Hendy DA, Ontiveros-Padilla L, Ehrenzeller SA, Islam MJ, Pena ES, Carlock MA, Ross TM, Bachelder EM, Ainslie KM. Induction of Antigen-Specific Tolerance in a Multiple Sclerosis Model without Broad Immunosuppression. ACS NANO 2025; 19:3764-3780. [PMID: 39812522 DOI: 10.1021/acsnano.4c14698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Multiple sclerosis (MS) is a severe autoimmune disorder that wreaks havoc on the central nervous system, leading to a spectrum of motor and cognitive impairments. There is no cure, and current treatment strategies rely on broad immunosuppression, leaving patients vulnerable to infections. To address this problem, our approach aims to induce antigen-specific tolerance, a much-needed shift in MS therapy. We have engineered a tolerogenic therapy consisting of spray-dried particles made of a degradable biopolymer, acetalated dextran, and loaded with an antigenic peptide and tolerizing drug, rapamycin (Rapa). After initial characterization and optimization, particles were tested in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis model of MS. Representing the earliest possible time of diagnosis, mice were treated at symptom onset in an early therapeutic model, where particles containing MOG and particles containing Rapa+MOG evoked significant reductions in clinical score. Particles were then applied to a highly clinically relevant late therapeutic model during peak disease, where MOG particles and Rapa+MOG particles each elicited a dramatic therapeutic effect, reversing hind limb paralysis and restoring fully functional limbs. To confirm the antigen specificity of our therapy, we immunized mice against the influenza antigen hemagglutinin (HA) and treated them with MOG particles or Rapa+MOG particles. The particles did not suppress antibody responses against HA. Our findings underscore the potential of this particle-based therapy to reverse autoimmunity in disease-relevant models without compromising immune competence, setting it apart from existing treatments.
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Affiliation(s)
- Rebeca T Stiepel
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Sean R Simpson
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Nicole Rose Lukesh
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Denzel D Middleton
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Dylan A Hendy
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Luis Ontiveros-Padilla
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Stephen A Ehrenzeller
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Md Jahirul Islam
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Erik S Pena
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, United States
| | - Michael A Carlock
- Florida Research and Innovation Center, Port Saint, Cleveland Clinic Florida, Port St. Lucie, Florida 34987, United States
| | - Ted M Ross
- Florida Research and Innovation Center, Port Saint, Cleveland Clinic Florida, Port St. Lucie, Florida 34987, United States
- Center for Vaccines and Immunology, University of Georgia, Athens, Georgia 30602, United States
- Department of Infectious Diseases, University of Georgia, Athens, Georgia 30602, United States
| | - Eric M Bachelder
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Kristy M Ainslie
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, United States
- Department of Microbiology & Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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Arve-Butler S, Moorman CD. A comprehensive overview of tolerogenic vaccine adjuvants and their modes of action. Front Immunol 2024; 15:1494499. [PMID: 39759532 PMCID: PMC11695319 DOI: 10.3389/fimmu.2024.1494499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/29/2024] [Indexed: 01/07/2025] Open
Abstract
Tolerogenic vaccines represent a therapeutic approach to induce antigen-specific immune tolerance to disease-relevant antigens. As general immunosuppression comes with significant side effects, including heightened risk of infections and reduced anti-tumor immunity, antigen-specific tolerance by vaccination would be game changing in the treatment of immunological conditions such as autoimmunity, anti-drug antibody responses, transplantation rejection, and hypersensitivity. Tolerogenic vaccines induce antigen-specific tolerance by promoting tolerogenic antigen presenting cells, regulatory T cells, and regulatory B cells, or by suppressing or depleting antigen-specific pathogenic T and B cells. The design of tolerogenic vaccines vary greatly, but they all deliver a disease-relevant antigen with or without a tolerogenic adjuvant. Tolerogenic adjuvants are molecules which mediate anti-inflammatory or immunoregulatory effects and enhance vaccine efficacy by modulating the immune environment to favor a tolerogenic immune response to the vaccine antigen. Tolerogenic adjuvants act through several mechanisms, including immunosuppression, modulation of cytokine signaling, vitamin signaling, and modulation of immunological synapse signaling. This review seeks to provide a comprehensive examination of tolerogenic adjuvants currently utilized in tolerogenic vaccines, describing their mechanism of action and examples of their use in human clinical trials and animal models of disease.
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Affiliation(s)
- Sabine Arve-Butler
- Amgen R&D Postdoctoral Fellows Program, Amgen Inc, South San Francisco, CA, United States
- Amgen Research, Amgen Inc., South San Francisco, CA, United States
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6
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Tunbridge MJ, Luo X, Thomson AW. Negative Vaccination Strategies for Promotion of Transplant Tolerance. Transplantation 2024; 108:1715-1729. [PMID: 38361234 PMCID: PMC11265982 DOI: 10.1097/tp.0000000000004911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
Organ transplantation requires the use of immunosuppressive medications that lack antigen specificity, have many adverse side effects, and fail to induce immunological tolerance to the graft. The safe induction of tolerance to allogeneic tissue without compromising host responses to infection or enhancing the risk of malignant disease is a major goal in transplantation. One promising approach to achieve this goal is based on the concept of "negative vaccination." Vaccination (or actively acquired immunity) involves the presentation of both a foreign antigen and immunostimulatory adjuvant to the immune system to induce antigen-specific immunity. By contrast, negative vaccination, in the context of transplantation, involves the delivery of donor antigen before or after transplantation, together with a "negative adjuvant" to selectively inhibit the alloimmune response. This review will explore established and emerging negative vaccination strategies for promotion of organ or pancreatic islet transplant tolerance. These include donor regulatory myeloid cell infusion, which has progressed to early-phase clinical trials, apoptotic donor cell infusion that has advanced to nonhuman primate models, and novel nanoparticle antigen-delivery systems.
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Affiliation(s)
- Matthew J. Tunbridge
- Adelaide Medical School, University of Adelaide, Adelaide, Australia
- Department of Medicine (Nephrology), Duke University Medical Center, Durham, North Carolina, USA
| | - Xunrong Luo
- Department of Medicine (Nephrology), Duke University Medical Center, Durham, North Carolina, USA
| | - Angus W. Thomson
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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7
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Genito CJ, Darwitz BP, Reber CP, Moorman NJ, Graves CL, Monteith AJ, Thurlow LR. mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection. mBio 2024; 15:e0086224. [PMID: 38767353 PMCID: PMC11324022 DOI: 10.1128/mbio.00862-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 04/15/2024] [Indexed: 05/22/2024] Open
Abstract
Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.
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Affiliation(s)
- Christopher J. Genito
- Division of Oral and
Craniofacial Health Sciences, Adams School of Dentistry, University of
North Carolina at Chapel Hill,
Chapel Hill, North Carolina,
USA
| | - Benjamin P. Darwitz
- Department of
Microbiology and Immunology, School of Medicine, University of North
Carolina at Chapel Hill, Chapel
Hill, North Carolina, USA
| | - Callista P. Reber
- Department of
Microbiology, University of Tennessee,
Knoxville, Tennessee,
USA
| | - Nathaniel J. Moorman
- Department of
Microbiology and Immunology, School of Medicine, University of North
Carolina at Chapel Hill, Chapel
Hill, North Carolina, USA
| | - Christina L. Graves
- Division of Oral and
Craniofacial Health Sciences, Adams School of Dentistry, University of
North Carolina at Chapel Hill,
Chapel Hill, North Carolina,
USA
| | - Andrew J. Monteith
- Department of
Microbiology, University of Tennessee,
Knoxville, Tennessee,
USA
| | - Lance R. Thurlow
- Division of Oral and
Craniofacial Health Sciences, Adams School of Dentistry, University of
North Carolina at Chapel Hill,
Chapel Hill, North Carolina,
USA
- Department of
Microbiology and Immunology, School of Medicine, University of North
Carolina at Chapel Hill, Chapel
Hill, North Carolina, USA
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Naseri B, Mardi A, Khosrojerdi A, Baghbani E, Aghebati-Maleki L, Hatami-Sadr A, Heris JA, Eskandarzadeh S, Kafshdouz M, Alizadeh N, Baradaran B. Everolimus treatment enhances inhibitory immune checkpoint molecules' expression in monocyte-derived dendritic cells. Hum Immunol 2024; 85:110798. [PMID: 38569354 DOI: 10.1016/j.humimm.2024.110798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Antigen-specific T-cell immunity is provided by dendritic cells (DCs), which are specialized antigen-presenting cells. Furthermore, they establish a link between innate and adaptive immune responses. Currently, DC modification is a new approach for the therapy of several disorders. During solid organ transplantation, Everolimus, which is a mammalian target of rapamycin (mTOR) inhibitor, was initially utilized to suppress the immune system's functionality. Due to the intervention of Everolimus in various signaling pathways in cells and its modulatory properties on the immune system, this study aims to investigate the effect of treatment with Everolimus on the maturation and expression of immune checkpoint genes in monocyte-derived DCs. METHODS To isolate monocytes from PBMCs, the CD14 marker was used via the MACS method. Monocytes were cultured and induced to differentiate into monocyte-derived DCs by utilizing GM-CSF and IL-4 cytokines. On the fifth day, immature DCs were treated with Everolimus and incubated for 24 h. On the sixth day, the flow cytometry technique was used to investigate the effect of Everolimus on the phenotypic characteristics of DCs. In the end, the expression of immune checkpoint genes in both the Everolimus-treated and untreated DCs groups was assessed using the real-time PCR method. RESULTS The findings of this research demonstrated that the administration of Everolimus to DCs led to a notable rise in human leukocyte antigen (HLA)-DR expression and a decrease in CD11c expression. Furthermore, there was a significant increase in the expression of immune checkpoint molecules, namely CTLA-4, VISTA, PD-L1, and BTLA, in DCs treated with Everolimus. CONCLUSION The findings of this study show that Everolimus can target DCs and affect their phenotype and function in order to shift them toward a partially tolerogenic state. However, additional research is required to gain a comprehensive understanding of the precise impact of Everolimus on the activation status of DCs.
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Affiliation(s)
- Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Elham Baghbani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | | | | | - Mahshid Kafshdouz
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Kalinina O, Minter LM, Sperling AI, Hollinger MK, Le P, Osborne BA, Zhang S, Stiff P, Knight KL. Exopolysaccharide-Treated Dendritic Cells Effectively Ameliorate Acute Graft-versus-Host Disease. Transplant Cell Ther 2024; 30:79.e1-79.e10. [PMID: 37924979 DOI: 10.1016/j.jtct.2023.10.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023]
Abstract
Graft-versus-host disease (GVHD) is a primary and often lethal complication of allogenic hematopoietic stem cell transplantation (HSCT). Prophylactic regimens for GVHD are given as standard pretransplantation therapy; however, up to 50% of these patients develop acute GVHD (aGVHD) and require additional immunosuppressive intervention. Using a mouse GVHD model, we previously showed that injecting mice with exopolysaccharide (EPS) from Bacillus subtilis prior to GVHD induction significantly increased 80-day survival after transplantation of complete allogeneic major histocompatibility complex-mismatched cells. To ask whether EPS might also inhibit GVHD in humans, we used humanized NSG-HLA-A2 mice and induced GVHD by i.v. injection of A2neg human peripheral blood mononuclear cells (PBMCs). Because we could not inject human donors with EPS, we transferred EPS-pretreated dendritic cells (DCs) to inhibit aGVHD. We derived these DCs from CD34+ human cord blood cells, treated them with EPS, and then injected them together with PBMCs into the NSG-HLA-A2 mice. We found that all mice that received untreated DCs were dead by day 35, whereas 25% of mice receiving EPS-treated DCs (EPS-DCs) survived. This DC cell therapy could be readily translatable to humans, because we can generate large numbers of human EPS-DCs and use them as an "off the shelf" treatment for patients undergoing HSCT.
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Affiliation(s)
- Olga Kalinina
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
| | - Lisa M Minter
- Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, Massachusetts
| | - Anne I Sperling
- Department of Medicine, Pulmonary Division, and Carter Center for Immunology, University of Virginia, Charlottesville, Virginia
| | | | - Phong Le
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
| | - Barbara A Osborne
- Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst, Massachusetts; HasenTech, LLC, Leverett, Massachusetts
| | - Shubin Zhang
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
| | - Patrick Stiff
- Hematology-Oncology Division, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
| | - Katherine L Knight
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; HasenTech, LLC, Leverett, Massachusetts.
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10
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Chang Y, Xiong W, Zou C, Zeng P, Hou J, Muhitdinov B, Shen Y, Huang Y, Guo S. Mitigation of Anti-Drug Antibody Production for Augmenting Anticancer Efficacy of Therapeutic Protein via Co-Injection of Nano-Rapamycin. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2303916. [PMID: 37705134 DOI: 10.1002/smll.202303916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/08/2023] [Indexed: 09/15/2023]
Abstract
The induction of anti-drug antibody (ADA) is a formidable challenge for protein-based therapy. Trichosanthin (TCS) as a class of ribosome-inactivating proteins is widely studied in tumor treatment. However, the immunogenicity can induce the formation of ADA, which can cause hypersensitivity reactions and neutralize the efficacy of TCS, thus limiting its clinical application in cancer therapy. Here, a promising solution to this issue is presented by co-administration of the rapamycin nanoparticles and TCS. PEGylated rapamycin amphiphilic molecule is designed and synthesized as a prodrug and a delivery carrier, which can self-assemble into a nanoparticle system with encapsulation of free rapamycin, a hydrophobic drug. It is found that co-injection of the PEGylated rapamycin nanoparticles and TCS could mitigate the formation of anti-TCS antibody via inducing durable immunological tolerance. Importantly, the combination of TCS and the rapamycin nanoparticles has an enhanced effect on inhibit the growth of breast cancer. This work provides a promising approach for protein toxin-based anticancer therapy and for promoting the clinical translation.
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Affiliation(s)
- Ya Chang
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Wei Xiong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
| | - Chenming Zou
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ping Zeng
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jiazhen Hou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, China
| | - Bahtiyor Muhitdinov
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Institute of Bioorganic Chemistry, Uzbekistan Academy of Sciences, Tashkent, 100125, Uzbekistan
| | - Yuanyuan Shen
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yongzhuo Huang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shengrong Guo
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
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11
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Perpiñán E, Sanchez-Fueyo A, Safinia N. Immunoregulation: the interplay between metabolism and redox homeostasis. FRONTIERS IN TRANSPLANTATION 2023; 2:1283275. [PMID: 38993920 PMCID: PMC11235320 DOI: 10.3389/frtra.2023.1283275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/13/2023] [Indexed: 07/13/2024]
Abstract
Regulatory T cells are fundamental for the induction and maintenance of immune homeostasis, with their dysfunction resulting in uncontrolled immune responses and tissue destruction predisposing to autoimmunity, transplant rejection and several inflammatory and metabolic disorders. Recent discoveries have demonstrated that metabolic processes and mitochondrial function are critical for the appropriate functioning of these cells in health, with their metabolic adaptation, influenced by microenvironmental factors, seen in several pathological processes. Upon activation regulatory T cells rearrange their oxidation-reduction (redox) system, which in turn supports their metabolic reprogramming, adding a layer of complexity to our understanding of cellular metabolism. Here we review the literature surrounding redox homeostasis and metabolism of regulatory T cells to highlight new mechanistic insights of these interlinked pathways in immune regulation.
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Affiliation(s)
| | | | - N. Safinia
- Department of Inflammation Biology, School of Immunology and Microbial Sciences, Institute of Liver Studies, James Black Centre, King’s College London, London, United Kingdom
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12
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Czaja AJ. Introducing Molecular Chaperones into the Causality and Prospective Management of Autoimmune Hepatitis. Dig Dis Sci 2023; 68:4098-4116. [PMID: 37755606 PMCID: PMC10570239 DOI: 10.1007/s10620-023-08118-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 09/18/2023] [Indexed: 09/28/2023]
Abstract
Molecular chaperones influence the immunogenicity of peptides and the activation of effector T cells, and their pathogenic roles in autoimmune hepatitis are unclear. Heat shock proteins are pivotal in the processing and presentation of peptides that activate CD8+ T cells. They can also induce regulatory B and T cells and promote immune tolerance. Tapasin and the transporter associated with antigen processing-binding protein influence the editing and loading of high-affinity peptides for presentation by class I molecules of the major histocompatibility complex. Their over-expression could enhance the autoimmune response, and their deficiency could weaken it. The lysosome-associated membrane protein-2a isoform in conjunction with heat shock cognate 70 supports the importation of cytosolic proteins into lysosomes. Chaperone-mediated autophagy can then process the peptides for activation of CD4+ T cells. Over-expression of autophagy in T cells may also eliminate negative regulators of their activity. The human leukocyte antigen B-associated transcript three facilitates the expression of class II peptide receptors, inhibits T cell apoptosis, prevents T cell exhaustion, and sustains the immune response. Immunization with heat shock proteins has induced immune tolerance in experimental models and humans with autoimmune disease by inducing regulatory T cells. Therapeutic manipulation of other molecular chaperones may promote T cell exhaustion and induce tolerogenic dendritic cells. In conclusion, molecular chaperones constitute an under-evaluated family of ancillary proteins that could affect the occurrence, severity, and outcome of autoimmune hepatitis. Clarification of their contributions to the immune mechanisms and clinical activity of autoimmune hepatitis could have therapeutic implications.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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13
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Won SY, Kinney SM, Sefton MV. Neutrophil depletion for early allogeneic islet survival in a methacrylic acid (MAA) copolymer-induced, vascularized subcutaneous space. FRONTIERS IN TRANSPLANTATION 2023; 2:1244093. [PMID: 38993844 PMCID: PMC11235352 DOI: 10.3389/frtra.2023.1244093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 10/03/2023] [Indexed: 07/13/2024]
Abstract
Islet transplantation is a promising treatment for type I diabetes (T1D). Despite the high loss of islets during transplantation, current islet transplant protocols continue to rely on portal vein infusion and intrahepatic engraftment. Because of the risk of portal vein thrombosis and the loss of islets to instant blood mediated inflammatory reaction (IBMIR), other transplantation sites like the subcutaneous space have been pursued for its large transplant volume, accessibility, and amenability for retrieval. To overcome the minimal vasculature of the subcutaneous space, prevascularization approaches or vascularizing biomaterials have been used to subcutaneously deliver islets into diabetic mice to return them to normoglycemia. Previous vascularization methods have relied on a 4 to 6 week prevascularization timeframe. Here we show that a vascularizing MAA-coated silicone tube can generate sufficient vasculature in 2 to 3 weeks to support a therapeutic dose of islets in mice. In order to fully harness the potential of this prevascularized site, we characterize the unique, subcutaneous immune response to allogeneic islets in the first 7 days following transplantation, a critical stage in successful engraftment. We identify neutrophils as a specific cellular target, a previously overlooked cell in the context of subcutaneous allogeneic islet transplantation. By perioperatively depleting neutrophils, we show that neutrophils are a key, innate immune cell target for successful early engraftment of allogeneic islets in a prevascularized subcutaneous site.
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Affiliation(s)
- So-Yoon Won
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Sean M Kinney
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Michael V Sefton
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
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14
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Zhang F, Cheng T, Zhang SX. Mechanistic target of rapamycin (mTOR): a potential new therapeutic target for rheumatoid arthritis. Arthritis Res Ther 2023; 25:187. [PMID: 37784141 PMCID: PMC10544394 DOI: 10.1186/s13075-023-03181-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/25/2023] [Indexed: 10/04/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic synovitis and bone destruction. Proinflammatory cytokines activate pathways of immune-mediated inflammation, which aggravates RA. The mechanistic target of rapamycin (mTOR) signaling pathway associated with RA connects immune and metabolic signals, which regulates immune cell proliferation and differentiation, macrophage polarization and migration, antigen presentation, and synovial cell activation. Therefore, therapy strategies targeting mTOR have become an important direction of current RA treatment research. In the current review, we summarize the biological functions of mTOR, its regulatory effects on inflammation, and the curative effects of mTOR inhibitors in RA, thus providing references for the development of RA therapeutic targets and new drugs.
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Affiliation(s)
- Fen Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, 030001, Shanxi Province, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Ting Cheng
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, 030001, Shanxi Province, China
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Xinghualing District, Taiyuan, 030001, Shanxi Province, China.
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China.
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China.
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15
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Li JSY, Robertson H, Trinh K, Raghubar AM, Nguyen Q, Matigian N, Patrick E, Thomson AW, Mallett AJ, Rogers NM. Tolerogenic dendritic cells protect against acute kidney injury. Kidney Int 2023; 104:492-507. [PMID: 37244471 DOI: 10.1016/j.kint.2023.05.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 04/12/2023] [Accepted: 05/11/2023] [Indexed: 05/29/2023]
Abstract
Ischemia reperfusion injury is a common precipitant of acute kidney injury that occurs following disrupted perfusion to the kidney. This includes blood loss and hemodynamic shock, as well as during retrieval for deceased donor kidney transplantation. Acute kidney injury is associated with adverse long-term clinical outcomes and requires effective interventions that can modify the disease process. Immunomodulatory cell therapies such as tolerogenic dendritic cells remain a promising tool, and here we tested the hypothesis that adoptively transferred tolerogenic dendritic cells can limit kidney injury. The phenotypic and genomic signatures of bone marrow-derived syngeneic or allogeneic, Vitamin-D3/IL-10-conditioned tolerogenic dendritic cells were assessed. These cells were characterized by high PD-L1:CD86, elevated IL-10, restricted IL-12p70 secretion and a suppressed transcriptomic inflammatory profile. When infused systemically, these cells successfully abrogated kidney injury without modifying infiltrating inflammatory cell populations. They also provided protection against ischemia reperfusion injury in mice pre-treated with liposomal clodronate, suggesting the process was regulated by live, rather than reprocessed cells. Co-culture experiments and spatial transcriptomic analysis confirmed reduced kidney tubular epithelial cell injury. Thus, our data provide strong evidence that peri-operatively administered tolerogenic dendritic cells have the ability to protect against acute kidney injury and warrants further exploration as a therapeutic option. This technology may provide a clinical advantage for bench-to-bedside translation to affect patient outcomes.
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Affiliation(s)
- Jennifer S Y Li
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia; Sydney Medical School, Faculty of Health and Medicine, University of Sydney, Sydney, New South Wales, Australia; Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Harry Robertson
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia; School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia
| | - Katie Trinh
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Arti M Raghubar
- Institute for Molecular Bioscience, the University of Queensland, Brisbane, Queensland, Australia
| | - Quan Nguyen
- Institute for Molecular Bioscience, the University of Queensland, Brisbane, Queensland, Australia
| | - Nicholas Matigian
- Institute for Molecular Bioscience, the University of Queensland, Brisbane, Queensland, Australia; Queensland Cyber Infrastructure Foundation Bioinformatics, Brisbane, Queensland, Australia
| | - Ellis Patrick
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia; School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia
| | - Angus W Thomson
- Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Andrew J Mallett
- Institute for Molecular Bioscience, the University of Queensland, Brisbane, Queensland, Australia; Department of Renal Medicine, Townsville University Hospital, Townsville, Queensland, Australia; College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia; Sydney Medical School, Faculty of Health and Medicine, University of Sydney, Sydney, New South Wales, Australia; Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
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16
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Zhao Y, Gao C, Liu L, Wang L, Song Z. The development and function of human monocyte-derived dendritic cells regulated by metabolic reprogramming. J Leukoc Biol 2023; 114:212-222. [PMID: 37232942 DOI: 10.1093/jleuko/qiad062] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 04/15/2023] [Accepted: 04/28/2023] [Indexed: 05/27/2023] Open
Abstract
Human monocyte-derived dendritic cells (moDCs) that develop from monocytes play a key role in innate inflammatory responses as well as T cell priming. Steady-state moDCs regulate immunogenicity and tolerogenicity by changing metabolic patterns to participate in the body's immune response. Increased glycolytic metabolism after danger signal induction may strengthen moDC immunogenicity, whereas high levels of mitochondrial oxidative phosphorylation were associated with the immaturity and tolerogenicity of moDCs. In this review, we discuss what is currently known about differential metabolic reprogramming of human moDC development and distinct functional properties.
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Affiliation(s)
- Ying Zhao
- Department of Dermatology, Southwest Hospital, Army Medical University, 30 Gaotanyan Street, District Shapingba, Chongqing, 400038, China
| | - Cuie Gao
- Department of Dermatology, Southwest Hospital, Army Medical University, 30 Gaotanyan Street, District Shapingba, Chongqing, 400038, China
| | - Lu Liu
- Department of Dermatology, Southwest Hospital, Army Medical University, 30 Gaotanyan Street, District Shapingba, Chongqing, 400038, China
| | - Li Wang
- Institute of Immunology, College of Basic Medical Sciences, Army Medical University, Chongqing, China
| | - Zhiqiang Song
- Department of Dermatology, Southwest Hospital, Army Medical University, 30 Gaotanyan Street, District Shapingba, Chongqing, 400038, China
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17
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Mak ML, Reid KT, Crome SQ. Protective and pathogenic functions of innate lymphoid cells in transplantation. Clin Exp Immunol 2023; 213:23-39. [PMID: 37119279 PMCID: PMC10324558 DOI: 10.1093/cei/uxad050] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/27/2023] [Accepted: 04/28/2023] [Indexed: 05/01/2023] Open
Abstract
Innate lymphoid cells (ILCs) are a family of lymphocytes with essential roles in tissue homeostasis and immunity. Along with other tissue-resident immune populations, distinct subsets of ILCs have important roles in either promoting or inhibiting immune tolerance in a variety of contexts, including cancer and autoimmunity. In solid organ and hematopoietic stem cell transplantation, both donor and recipient-derived ILCs could contribute to immune tolerance or rejection, yet understanding of protective or pathogenic functions are only beginning to emerge. In addition to roles in directing or regulating immune responses, ILCs interface with parenchymal cells to support tissue homeostasis and even regeneration. Whether specific ILCs are tissue-protective or enhance ischemia reperfusion injury or fibrosis is of particular interest to the field of transplantation, beyond any roles in limiting or promoting allograft rejection or graft-versus host disease. Within this review, we discuss the current understanding of ILCs functions in promoting immune tolerance and tissue repair at homeostasis and in the context of transplantation and highlight where targeting or harnessing ILCs could have applications in novel transplant therapies.
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Affiliation(s)
- Martin L Mak
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | - Kyle T Reid
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | - Sarah Q Crome
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada
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18
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Zahorchak AF, DeRiggi ML, Muzzio JL, Sutherland V, Humar A, Lakkis FG, Hsu YMS, Thomson AW. Manufacturing and validation of Good Manufacturing Practice-compliant regulatory dendritic cells for infusion into organ transplant recipients. Cytotherapy 2023; 25:432-441. [PMID: 36639251 DOI: 10.1016/j.jcyt.2022.11.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 10/28/2022] [Accepted: 11/18/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND AIMS Regulatory (or "tolerogenic") dendritic cells (DCregs) are a highly promising, innovative cell therapy for the induction or restoration of antigen-specific tolerance in immune-mediated inflammatory disorders. These conditions include organ allograft rejection, graft-versus-host disease following bone marrow transplantation and various autoimmune disorders. DCregs generated for adoptive transfer have potential to reduce patients' dependence on non-specific immunosuppressive drugs that can induce serious side effects and enhance the risk of infection and certain types of cancer. Here, our aim was to provide a detailed account of our experience manufacturing and validating comparatively large numbers of Good Manufacturing Practice-grade DCregs for systemic (intravenous) infusion into 28 organ (liver) transplant recipients and to discuss factors that influence the satisfaction of release criteria and attainment of target cell numbers. RESULTS DCregs were generated in granulocyte-macrophage colony stimulating factor and interleukin (IL)-4 from elutriated monocyte fractions isolated from non-mobilized leukapheresis products of consenting healthy adult prospective liver transplant donors. Vitamin D3 was added on day 0 and 4 and IL-10 on day 4 during the 7-day culture period. Release and post-release criteria included cell viability, purity, phenotype, sterility and functional assessment. The overall conversion rate of monocytes to DCregs was 28 ± 8.2%, with 94 ± 5.1% product viability. The mean cell surface T-cell co-inhibitory to co-stimulatory molecule (programmed death ligand-1:CD86) mean fluorescence intensity ratio was 3.9 ± 2.2, and the mean ratio of anti-inflammatory:pro-inflammatory cytokine product (IL-10:IL-12p70) secreted upon CD40 ligation was 60 ± 63 (median = 40). The mean total number of DCregs generated from a single leukapheresis product (n = 25 donors) and from two leukapheresis products (n = 3 donors) was 489 ± 223 × 106 (n = 28). The mean total number of DCregs infused was 5.9 ± 2.8 × 106 per kg body weight. DCreg numbers within a target cell range of 2.5-10 × 106/kg were achieved for 25 of 27 (92.6%) of products generated. CONCLUSIONS High-purity DCregs meeting a range of quality criteria were readily generated from circulating blood monocytes under Good Manufacturing Practice conditions to meet target cell numbers for infusion into prospective organ transplant recipients.
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Affiliation(s)
- Alan F Zahorchak
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Misty L DeRiggi
- Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Jennifer L Muzzio
- Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Veronica Sutherland
- Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
| | - Abhinav Humar
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Fadi G Lakkis
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yen-Michael S Hsu
- Immunologic Monitoring & Cellular Products Laboratory, University of Pittsburgh Hillman Cancer Center, Pittsburgh, Pennsylvania, USA; Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
| | - Angus W Thomson
- Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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19
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Zhang J, Wang X, Wang R, Chen G, Wang J, Feng J, Li Y, Yu Z, Xiao H. Rapamycin Treatment Alleviates Chronic GVHD-Induced Lupus Nephritis in Mice by Recovering IL-2 Production and Regulatory T Cells While Inhibiting Effector T Cells Activation. Biomedicines 2023; 11:biomedicines11030949. [PMID: 36979928 PMCID: PMC10045991 DOI: 10.3390/biomedicines11030949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/07/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
In this study, we test the therapeutic effects of rapamycin in a murine model of SLE-like experimental lupus nephritis induced by chronic graft-versus-host disease (cGVHD). Our results suggest that rapamycin treatment reduced autoantibody production, inhibited T lymphocyte and subsequent B cell activation, and reduced inflammatory cytokine and chemokine production, thereby protecting renal function and alleviating histological lupus nephritis by reducing the occurrence of albuminuria. To explore the potential mechanism of rapamycin's reduction of kidney damage in mice with lupus nephritis, a series of functional assays were conducted. As expected, rapamycin remarkably inhibited the lymphocytes' proliferation within the morbid mice. Interestingly, significantly increased proportions of peripheral CD4+FOXP3+ and CD4+CD25high T cells were observed in rapamycin-treated group animals, suggesting an up-regulation of regulatory T cells (Tregs) in the periphery by rapamycin treatment. Furthermore, consistent with the results regarding changes in mRNA abundance in kidney by real-time PCR analysis, intracellular cytokine staining demonstrated that rapamycin treatment remarkably diminished the secretion of Th1 and Th2 cytokines, including IFN-γ, IL-4 and IL-10, in splenocytes of the morbid mice. However, the production of IL-2 from splenocytes in rapamycin-treated mice was significantly higher than in the cells from control group animals. These findings suggest that rapamycin treatment might alleviate systemic lupus erythematosus (SLE)-like experimental lupus nephritis through the recovery of IL-2 production, which promotes the expansion of regulatory T cells while inhibiting effector T cell activation. Our studies demonstrated that, unlike other commonly used immunosuppressants, rapamycin does not appear to interfere with tolerance induction but permits the expansion and suppressive function of Tregs in vivo.
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Affiliation(s)
- Jilu Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
- Department of Biomedicine, Institute of Frontier Medical Sciences, Jilin University, Changchun 130021, China
| | - Xun Wang
- Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Renxi Wang
- Laboratory of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Beijing Institute of Brain Disorders, Capital Medical University, Ministry of Science and Technology, Beijing 100054, China
| | - Guojiang Chen
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Jing Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Jiannan Feng
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Yan Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Zuyin Yu
- Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - He Xiao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
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20
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Moreau A, Kervella D, Bouchet-Delbos L, Braudeau C, Saïagh S, Guérif P, Limou S, Moreau A, Bercegeay S, Streitz M, Sawitzki B, James B, Harden PN, Game D, Tang Q, Markmann JF, Roberts ISD, Geissler EK, Dréno B, Josien R, Cuturi MC, Blancho G, Branchereau J, Cantarovich D, Chapelet A, Dantal J, Deltombe C, Figueres L, Gaisne R, Garandeau C, Giral M, Gourraud-Vercel C, Hourmant M, Karam G, Kerleau C, Kervella D, Masset C, Meurette A, Ville S, Kandell C, Moreau A, Renaudin K, Delbos F, Walencik A, Devis A. A Phase I/IIa study of autologous tolerogenic dendritic cells immunotherapy in kidney transplant recipients. Kidney Int 2023; 103:627-637. [PMID: 36306921 DOI: 10.1016/j.kint.2022.08.037] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 08/16/2022] [Accepted: 08/19/2022] [Indexed: 11/09/2022]
Abstract
Kidney transplant survival is shortened by chronic rejection and side effects of standard immunosuppressive drugs. Cell-based immunotherapy with tolerogenic dendritic cells has long been recognized as a promising approach to reduce general immunosuppression. Published trials report the safety and the absence of therapy-related adverse reactions in patients treated with tolerogenic dendritic cells suffering from several inflammatory diseases. Here, we present the first phase I clinical trial results using human autologous tolerogenic dendritic cells (ATDC) in kidney transplantation. Eight patients received ATDC the day before transplantation in conjunction with standard steroids, mycophenolate mofetil and tacrolimus immunosuppression with an option to taper mycophenolate mofetil. ATDC preparations were manufactured in a Good Manufacturing Practice-compliant facility and fulfilled cell count, viability, purity and identity criteria for release. A control group of nine patients received the same standard immunosuppression, except basiliximab induction replaced ATDC therapy and mycophenolate tapering was not allowed. During the three-year follow-up, no deaths occurred and there was 100% graft survival. No significant increase of adverse events was associated with ATDC infusion. Episodes of rejection were observed in two patients from the ATDC group and one patient from the control group. However, all rejections were successfully treated by glucocorticoids. Mycophenolate was successfully reduced/stopped in five patients from the ATDC group, allowing tacrolimus monotherapy for two of them. Regarding immune monitoring, reduced CD8 T cell activation markers and increased Foxp3 expression were observed in the ATDC group. Thus, our results demonstrate ATDC administration safety in kidney-transplant recipients.
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Affiliation(s)
- Aurélie Moreau
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France.
| | - Delphine Kervella
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France; Centre Hospitalier Universitaire Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, Institut de Transplantation Urologie Nephrologie, Nantes, France
| | - Laurence Bouchet-Delbos
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France
| | - Cécile Braudeau
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France; Centre Hospitalier Universitaire Nantes, Nantes Université, Laboratoire d'Immunologie, Center for Immuno Monitoring Nantes Atlantic, Nantes, France
| | - Soraya Saïagh
- Centre Hospitalier Universitaire Nantes, Nantes Université, Unité de Thérapie Cellulaire et Génique Good Manufacturing Practice, Nantes, France
| | - Pierrick Guérif
- Centre Hospitalier Universitaire Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, Institut de Transplantation Urologie Nephrologie, Nantes, France
| | - Sophie Limou
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France
| | - Anne Moreau
- Centre Hospitalier Universitaire Nantes, Nantes Université, Laboratoire d'anatomopathologie, Nantes, France
| | - Sylvain Bercegeay
- Centre Hospitalier Universitaire Nantes, Nantes Université, Unité de Thérapie Cellulaire et Génique Good Manufacturing Practice, Nantes, France
| | - Mathias Streitz
- Institute of Medical Immunology, Charité University of Medicine, Berlin, Germany; Department of Experimental Animal Facilities and Biorisk Management, Friedrich-Loeffler Institut, Greifswald-Insel Riems, Greifswald, Germany
| | - Birgit Sawitzki
- Institute of Medical Immunology, Charité University of Medicine, Berlin, Germany
| | - Ben James
- Department of surgery, Division of Experimental Surgery, University of Regensburg, Regensburg, Germany
| | - Paul N Harden
- Oxford Transplant Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - David Game
- Department of Transplantation, Guys and St Thomas's Hospital NHS Trust, London, UK
| | - Qizhi Tang
- Department of Surgery, University of California San Francisco Transplantation Research Lab, University of California, San Francisco, California, USA
| | - James F Markmann
- Center for Transplantation Sciences, Mass General Hospital, Boston, Massachusetts, USA
| | - Ian S D Roberts
- Department of Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Edward K Geissler
- Department of surgery, Division of Experimental Surgery, University of Regensburg, Regensburg, Germany
| | - Brigitte Dréno
- Centre Hospitalier Universitaire Nantes, Nantes Université, Unité de Thérapie Cellulaire et Génique Good Manufacturing Practice, Nantes, France
| | - Régis Josien
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France; Centre Hospitalier Universitaire Nantes, Nantes Université, Laboratoire d'Immunologie, Center for Immuno Monitoring Nantes Atlantic, Nantes, France
| | - Maria-Cristina Cuturi
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France
| | - Gilles Blancho
- Inserm, Nantes Université, Centre Hospitalier Universitaire Nantes, Centre de Recherche Translationnelle en Transplantation et Immunologie, Unite Mixte de Recherche 1064, Institut de Transplantation Urologie Nephrologie, Nantes, France; Centre Hospitalier Universitaire Nantes, Nantes Université, Service de Néphrologie et d'immunologie clinique, Institut de Transplantation Urologie Nephrologie, Nantes, France.
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21
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Degechisa ST, Dabi YT. Leptin Deficiency May Influence the Divergence of Cell-Mediated Immunity Between Lepromatous and Tuberculoid Leprosy Patients. J Inflamm Res 2022; 15:6719-6728. [PMID: 36536644 PMCID: PMC9758981 DOI: 10.2147/jir.s389845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/29/2022] [Indexed: 04/28/2024] Open
Abstract
Leprosy is a disease caused by an intracellular bacillus bacterium called Mycobacterium leprae which lives and multiplies in the hosts' macrophages and Schwann cells. Depending on the degree of the host's cell-mediated immunity (CMI) response to the bacilli, the disease manifests itself in five clinical spectra ranging from polar tuberculoid (TT) to polar lepromatous leprosy (LL). A very high level of T helper 1 (Th1) driven bacilli-specific CMI is seen in the TT form, whereas this response is essentially nonexistent in the LL form. As a result, there is very low or absent bacillary load and localized nodular lesions in TT patients. On the contrary, LL patients presented with high bacillary load and generalized lesions due to low CMI response. The mechanism underlying this divergence of CMI response is not clearly elucidated yet. However, mounting evidence links it to an elevated number of Th1 and Th17 suppressing CD4+ CD25+ FOXP3+ T regulatory cells (Treg cells) which are abundantly found in LL than in TT patients. The predominance of these cells in LL patients is partly attributed to a deficiency of leptin, the cytokine-like peptide hormone, in these patients. Becausea normal level of leptin promotes the proliferation and preferential differentiation of effector T cells (Th1 and Th17) while inhibiting the growth and functional responsiveness of the Treg cells. In contrast, leptin deficiency or neutralization was reported to exert the opposite effect on Treg cells and effector T cells. Other smaller subsets of lymphocytes such as gamma delta (γδ) T cells and B regulatory cells are also modulated by leptin level in the pathogenesis of leprosy. Leptin may therefore regulate the divergence of CMI between TT and LL patients by regulating the homeostasis of effector T cells and Treg cells, and this review will examine the underlying mechanism for this.
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Affiliation(s)
- Sisay Teka Degechisa
- Medical Biochemistry Department, College of Health Sciences, Addis Ababa University, Addis Abeba, Ethiopia
- Medical Laboratory Science Department, College of Medicine and Health Sciences, Arba Minch University, Arba Minch, Ethiopia
| | - Yosef Tsegaye Dabi
- Medical Biochemistry Department, College of Health Sciences, Addis Ababa University, Addis Abeba, Ethiopia
- Medical Laboratory Science Department, Wollega University, Nekemte, Ethiopia
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22
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Sipka AS, Chandler TL, Weichhart T, Schuberth HJ, Mann S. Inhibition of mTOR in bovine monocyte derived macrophages and dendritic cells provides a potential mechanism for postpartum immune dysfunction in dairy cows. Sci Rep 2022; 12:15084. [PMID: 36064574 PMCID: PMC9445052 DOI: 10.1038/s41598-022-19295-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 08/26/2022] [Indexed: 11/29/2022] Open
Abstract
Dairy cattle experience a profound nutrient deficit postpartum that is associated with immune dysfunction characterized by heightened inflammation and reduced pathogen clearance. The activation of the central nutrient-sensing mTOR pathway is comparatively reduced in leukocytes of early postpartum dairy cows during this time of most pronounced nutrient deficit. We assessed the effect of pharmacological mTOR inhibition (Torin-1, rapamycin) on differentiation of monocyte derived classically (M1) and alternatively (M2) activated macrophages (MPh) and dendritic cells (moDC) from 12 adult dairy cows. Treatment with mTOR inhibitors generated M1 MPh with increased oxidative burst and expression of IL12 subunits but decreased phagocytosis and expression of IL1B, IL6, and IL10. In M2 MPh, treatment inhibited expression of regulatory features (CD163, ARG2, IL10) skewing the cells toward an M1-like phenotype. In moDC, mTOR inhibition increased expression of pro-inflammatory cytokines (IL12A, IL12B, IL1B, IL6) and surface CD80. In co-culture with mixed lymphocytes, mTOR-inhibited moDC exhibited a cytokine profile favoring a Th1 response with increased TNF and IFNG production and decreased IL10 concentrations. We conclude that mTOR inhibition in vitro promoted differentiation of inflammatory macrophages with reduced regulatory features and generation of Th1-favoring dendritic cells. These mechanisms could contribute to immune dysregulation in postpartum dairy cows.
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Affiliation(s)
- Anja S Sipka
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, 231 Farrier Road, Ithaca, NY, 14853, USA.
| | - Tawny L Chandler
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, 231 Farrier Road, Ithaca, NY, 14853, USA
| | - Thomas Weichhart
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Straße 10, 1090, Vienna, Austria
| | - Hans-Joachim Schuberth
- Institute for Immunology, University of Veterinary Medicine, Buenteweg 2, 30559, Hannover, Germany
| | - Sabine Mann
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, 231 Farrier Road, Ithaca, NY, 14853, USA.
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23
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Unbalanced IDO1/IDO2 Endothelial Expression and Skewed Keynurenine Pathway in the Pathogenesis of COVID-19 and Post-COVID-19 Pneumonia. Biomedicines 2022; 10:biomedicines10061332. [PMID: 35740354 PMCID: PMC9220124 DOI: 10.3390/biomedicines10061332] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 05/29/2022] [Accepted: 06/02/2022] [Indexed: 11/17/2022] Open
Abstract
Despite intense investigation, the pathogenesis of COVID-19 and the newly defined long COVID-19 syndrome are not fully understood. Increasing evidence has been provided of metabolic alterations characterizing this group of disorders, with particular relevance of an activated tryptophan/kynurenine pathway as described in this review. Recent histological studies have documented that, in COVID-19 patients, indoleamine 2,3-dioxygenase (IDO) enzymes are differentially expressed in the pulmonary blood vessels, i.e., IDO1 prevails in early/mild pneumonia and in lung tissues from patients suffering from long COVID-19, whereas IDO2 is predominant in severe/fatal cases. We hypothesize that IDO1 is necessary for a correct control of the vascular tone of pulmonary vessels, and its deficiency in COVID-19 might be related to the syndrome’s evolution toward vascular dysfunction. The complexity of this scenario is discussed in light of possible therapeutic manipulations of the tryptophan/kynurenine pathway in COVID-19 and post-acute COVID-19 syndromes.
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24
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Sipka A, Weichhart T, Mann S. Pharmacological inhibition of the mTOR pathway alters phenotype and cytokine expression in bovine monocyte-derived dendritic cells. Vet Immunol Immunopathol 2022; 249:110441. [PMID: 35597229 DOI: 10.1016/j.vetimm.2022.110441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/05/2022] [Accepted: 05/13/2022] [Indexed: 01/20/2023]
Abstract
Epidemiological studies have long demonstrated the association of nutrient status and immune dysfunction in dairy cows. Postpartum dairy cows experiencing a nutrient deficit show a propensity for increased inflammatory response, decreased pathogen clearance, and increased incidence of infectious disease. Studies in cows and other species show that the nutrient sensing mechanistic target of rapamycin (mTOR) signaling pathway could be one potential causal pathway connecting the deficit in nutrient availability and the heightened inflammatory response. Our objective was to investigate the effects of pharmacological mTOR pathway inhibition on phenotype and cytokine expression of bovine monocyte derived dendritic cells (moDC). We differentiated CD14+ monocytes from dairy cows (n = 14) into moDC in the presence or absence of first- or second-generation mTOR inhibitor rapamycin and PP242 (both 100 nM), respectively. On day seven cells were matured with E. coli lipopolysaccharide (LPS, 100 ng/mL) or left unstimulated to represent naïve moDC. Surface expression of CD14, CD40, CD80, and MHCII was measured via flow cytometry. We measured mRNA expression of IL10, IL12A, IL12B, and TNFα by rt-qPCR, and protein concentrations of IL-10 and TFN-α in cell culture supernatants with a bead-based multiplex assay. Cultures from ten cows successfully developed the moDC phenotype in culture without inhibitors, defined as increased surface expression of CD40, CD80, and MHCII compared with naïve moDC. Only data from these cows were considered for the results on effects of mTOR inhibitors. In naïve and mature moDC mTOR inhibition increased MHCII expression compared to controls. In mature moDC, in addition to MHCII, CD80 expression was increased compared with untreated LPS-stimulated controls. Expression of IL12A mRNA was upregulated in mature, mTOR inhibited moDC compared with untreated controls. In cell culture supernatants mTOR inhibition reduced IL-10 and increased TNF-α concentrations in naïve and mature moDCs compared with untreated controls. Overall rapamycin had a more consistent effect on altering phenotype and cytokine expression of moDC than PP242. In summary we observed an increased expression of co-stimulatory molecules and antigen presentation potential in mature moDC differentiated under mTOR inhibition, and a cytokine pattern that would potentially favor a Th1 type response. This study provides novel data indicating a role for mTOR signaling in bovine moDC phenotype and mediator profile. This proof-of-concept study demonstrates the role of the mTOR pathway in shaping the bovine immune response and may help to provide mechanistic insight and opportunities for modulation of the immune response during the nutrient deficit of early lactation.
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Affiliation(s)
- Anja Sipka
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
| | - Thomas Weichhart
- Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währinger Straße 10, 1090 Vienna, Austria
| | - Sabine Mann
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
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25
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Nording H, Sauter M, Lin C, Steubing R, Geisler S, Sun Y, Niethammer J, Emschermann F, Wang Y, Zieger B, Nieswandt B, Kleinschnitz C, Simon DI, Langer HF. Activated Platelets Upregulate β 2 Integrin Mac-1 (CD11b/CD18) on Dendritic Cells, Which Mediates Heterotypic Cell-Cell Interaction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:1729-1741. [PMID: 35277420 DOI: 10.4049/jimmunol.2100557] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 01/11/2022] [Indexed: 12/30/2022]
Abstract
Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell cross-talk are largely unknown. We evaluated the role of integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counterreceptor for platelet glycoprotein (GP) Ibα. In a dynamic coincubation model, we observed interaction of human platelets with monocyte-derived DCs, but also that platelet activation induced a sharp increase in heterotypic cell binding. Inhibition of CD11b or GPIbα led to significant reduction of DC adhesion to platelets in vitro independent of GPIIbIIIa, which we confirmed using platelets from Glanzmann thrombasthenia patients and transgenic mouse lines on C57BL/6 background (GPIbα-/-, IL4R-GPIbα-tg, and muMac1 mice). In vivo, inhibition or genetic deletion of CD11b and GPIbα induced a significant reduction of platelet-mediated DC adhesion to the injured arterial wall. Interestingly, only intravascular antiCD11b inhibited DC recruitment, suggesting a dynamic DC-platelet interaction. Indeed, we could show that activated platelets induced CD11b upregulation on Mg2+-preactivated DCs, which was related to protein kinase B (Akt) and dependent on P-selectin and P-selectin glycoprotein ligand 1. Importantly, specific pharmacological targeting of the GPIbα-Mac-1 interaction site blocked DC-platelet interaction in vitro and in vivo. These results demonstrate that cross-talk of platelets with DCs is mediated by GPIbα and Mac-1, which is upregulated on DCs by activated platelets in a P-selectin glycoprotein ligand 1-dependent manner.
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Affiliation(s)
- Henry Nording
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.,German Research Centre for Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany.,University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Manuela Sauter
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany.,University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Chaolan Lin
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Rebecca Steubing
- Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
| | - Sven Geisler
- Cell Analysis Core Facility, University of Lübeck, Lübeck, Germany
| | - Ying Sun
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
| | - Joel Niethammer
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Fréderic Emschermann
- Department of Cardiovascular Medicine, University Hospital, Eberhard Karls University, Tübingen, Germany
| | - Yunmei Wang
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Barbara Zieger
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
| | - Bernhard Nieswandt
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany; and
| | - Christoph Kleinschnitz
- Department of Neurology and Center for Translational and Behavioral Neurosciences, University Hospital Essen, Essen, Germany
| | - Daniel I Simon
- Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH.,University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Harald F Langer
- Cardioimmunology Group, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany; .,German Research Centre for Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany.,University Hospital, Medical Clinic II, University Heart Center Lübeck, Lübeck, Germany
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26
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Cho DH, Lee GY, An JH, Han SN. The Effects of 1,25(OH)2D3 treatment on Immune Responses and Intracellular Metabolic Pathways of Bone Marrow-Derived Dendritic Cells from Lean and Obese Mice. IUBMB Life 2021; 74:378-390. [PMID: 34962347 DOI: 10.1002/iub.2592] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/15/2021] [Indexed: 11/11/2022]
Abstract
Vitamin D affects differentiation, maturation, and activation of dendritic cells (DCs). Obesity-related immune dysfunction is associated with metabolic changes in immune cells. Objectives of the study are to investigate the effects of vitamin D and obesity on immune responses and markers related to immunometabolism of bone marrow-derived dendritic cells (BMDCs). Bone marrow cells (BMCs) were isolated from lean and obese mice, and BMDCs were generated by culturing BMCs with rmGM-CSF. BMDCs were treated with 1 or 10 nM of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and maturation was induced by LPS (50 ng/mL) stimulation for 24 h. Cell phenotypes, cytokine productions, and expression of proteins and genes involved in Akt/mTOR signaling pathway and glycolytic pathway were determined. 1,25(OH)2D3 treatment inhibited differentiation of BMDCs (CD11c+ %), expression of phenotypes related with DC function (MHC class II and CD86) and production of IL-12p70 in both lean and obese mice. The expression of PD-L1 and the ratio of IL-10/IL-12p70 were increased by 1,25(OH)2D3. With 1,25(OH)2D3 treatment, Akt/mTOR signaling pathway was suppressed, and expression of genes related to glycolysis (Glut1, Pfkfb4, Hif1A) was increased. The upregulation of glycolysis-related genes observed with 1,25(OH)2D3 treatment seems to be associated with the induction of tolerogenic features of BMDCs from lean and obese mice, and Hif1A seems to have a potential role in conveying the effect of 1,25(OH)2D3 on glycolysis. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Da Hye Cho
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
| | - Ga Young Lee
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
| | - Jeong Hee An
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
| | - Sung Nim Han
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea.,Research Institute of Human Ecology, Seoul National University, Seoul, Korea
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27
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Fu J, Lehmann CHK, Wang X, Wahlbuhl M, Allabauer I, Wilde B, Amon L, Dolff S, Cesnjevar R, Kribben A, Woelfle J, Rascher W, Hoyer PF, Dudziak D, Witzke O, Hoerning A. CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation. Sci Rep 2021; 11:23815. [PMID: 34893663 PMCID: PMC8664946 DOI: 10.1038/s41598-021-03115-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 11/08/2021] [Indexed: 12/20/2022] Open
Abstract
Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
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Affiliation(s)
- Jian Fu
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.,Department for Pediatric and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Loschgestrasse 15, 91054, Erlangen, Germany.,The Emergency and Trauma Center, The First Affiliated Hospital of Hai Nan Medical University, Haikou, China
| | - Christian H K Lehmann
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Research Module II, Hartmannstr. 14, 91052, Erlangen, Germany. .,Medical Immunology Campus and German Centre for Immuntherapy (Deutsches Zentrum für Immuntherapie-DZI) Erlangen, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany.
| | - Xinning Wang
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.,The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Mandy Wahlbuhl
- Department for Pediatric and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Loschgestrasse 15, 91054, Erlangen, Germany
| | - Ida Allabauer
- Department for Pediatric and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Loschgestrasse 15, 91054, Erlangen, Germany
| | - Benjamin Wilde
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Lukas Amon
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Research Module II, Hartmannstr. 14, 91052, Erlangen, Germany
| | - Sebastian Dolff
- Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany
| | - Robert Cesnjevar
- Department of Pediatric Cardiac Surgery, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), University Hospital Erlangen, Erlangen, Germany.,Department of Cardiac Surgery, Universitäts-Kinderspital Zürich, Zurich, Switzerland
| | - Andreas Kribben
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Joachim Woelfle
- Department for Pediatric and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Loschgestrasse 15, 91054, Erlangen, Germany
| | - Wolfgang Rascher
- Department for Pediatric and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Loschgestrasse 15, 91054, Erlangen, Germany
| | - Peter F Hoyer
- Department of Pediatrics II, Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Children's Hospital Essen, University Duisburg-Essen, Duisburg, Germany
| | - Diana Dudziak
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Research Module II, Hartmannstr. 14, 91052, Erlangen, Germany.,Medical Immunology Campus and German Centre for Immuntherapy (Deutsches Zentrum für Immuntherapie-DZI) Erlangen, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, West German Centre of Infectious Diseases, Universitätsmedizin Essen, University Duisburg-Essen, Essen, Germany
| | - André Hoerning
- Department for Pediatric and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Loschgestrasse 15, 91054, Erlangen, Germany. .,Department of Pediatrics II, Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Children's Hospital Essen, University Duisburg-Essen, Duisburg, Germany.
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28
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Li J, Thomson AW, Rogers NM. Myeloid and Mesenchymal Stem Cell Therapies for Solid Organ Transplant Tolerance. Transplantation 2021; 105:e303-e321. [PMID: 33756544 PMCID: PMC8455706 DOI: 10.1097/tp.0000000000003765] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Transplantation is now performed globally as a routine procedure. However, the increased demand for donor organs and consequent expansion of donor criteria has created an imperative to maximize the quality of these gains. The goal is to balance preservation of allograft function against patient quality-of-life, despite exposure to long-term immunosuppression. Elimination of immunosuppressive therapy to avoid drug toxicity, with concurrent acceptance of the allograft-so-called operational tolerance-has proven elusive. The lack of recent advances in immunomodulatory drug development, together with advances in immunotherapy in oncology, has prompted interest in cell-based therapies to control the alloimmune response. Extensive experimental work in animals has characterized regulatory immune cell populations that can induce and maintain tolerance, demonstrating that their adoptive transfer can promote donor-specific tolerance. An extension of this large body of work has resulted in protocols for manufacture, as well as early-phase safety and feasibility trials for many regulatory cell types. Despite the excitement generated by early clinical trials in autoimmune diseases and organ transplantation, there is as yet no clinically validated, approved regulatory cell therapy for transplantation. In this review, we summarize recent advances in this field, with a focus on myeloid and mesenchymal cell therapies, including current understanding of the mechanisms of action of regulatory immune cells, and clinical trials in organ transplantation using these cells as therapeutics.
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Affiliation(s)
- Jennifer Li
- Center of Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Angus W Thomson
- Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Natasha M Rogers
- Center of Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
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29
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Machcińska M, Kotur M, Jankowska A, Maruszewska-Cheruiyot M, Łaski A, Kotkowska Z, Bocian K, Korczak-Kowalska G. Cyclosporine A, in Contrast to Rapamycin, Affects the Ability of Dendritic Cells to Induce Immune Tolerance Mechanisms. Arch Immunol Ther Exp (Warsz) 2021; 69:27. [PMID: 34632525 PMCID: PMC8502748 DOI: 10.1007/s00005-021-00632-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/16/2021] [Indexed: 12/25/2022]
Abstract
Following organ transplantation, it is essential that immune tolerance is induced in the graft recipient to reduce the risk of rejection and avoid complications associated with the long-term use of immunosuppressive drugs. Immature dendritic cells (DCs) are considered to promote transplant tolerance and may minimize the risk of graft rejection. The aim of the study was to evaluate the effects of immunosuppressive agents: rapamycin (Rapa) and cyclosporine A (CsA) on generation of human tolerogenic DCs (tolDCs) and also to evaluate the ability of these cells to induce mechanisms of immune tolerance. tolDCs were generated in the environment of Rapa or CsA. Next, we evaluated the effects of these agents on surface phenotypes (CD11c, MHC II, CD40, CD80, CD83, CD86, CCR7, TLR2, TLR4), cytokine production (IL-4, IL-6, IL-10, IL-12p70, TGF-β), phagocytic capacity and resistant to lipopolysaccharide activation of these DCs. Moreover, we assessed ability of such tolDCs to induce T cell activation and apoptosis, Treg differentiation and production of Th1- and Th2-characteristic cytokine profile. Data obtained in this study demonstrate that rapamycin is effective at generating maturation-resistant tolDCs, however, does not change the ability of these cells to induce mechanisms of immune tolerance. In contrast, CsA affects the ability of these cells to induce mechanisms of immune tolerance, but is not efficient at generating maturation-resistant tolDCs.
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Affiliation(s)
- Maja Machcińska
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland. .,Present address: Laboratory of Parasitology, General Karol Kaczkowski Military Institute of Hygiene and Epidemiology, Warsaw, Poland.
| | - Monika Kotur
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Aleksandra Jankowska
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Marta Maruszewska-Cheruiyot
- Laboratory of Parasitology, General Karol Kaczkowski Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Artur Łaski
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Zuzanna Kotkowska
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Katarzyna Bocian
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Grażyna Korczak-Kowalska
- Department of Immunology, Institute of Functional Biology and Ecology, Faculty of Biology, University of Warsaw, Warsaw, Poland
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30
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Safinia N, Vaikunthanathan T, Lechler RI, Sanchez‐Fueyo A, Lombardi G. Advances in Liver Transplantation: where are we in the pursuit of transplantation tolerance? Eur J Immunol 2021; 51:2373-2386. [PMID: 34375446 PMCID: PMC10015994 DOI: 10.1002/eji.202048875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 06/07/2021] [Accepted: 07/23/2021] [Indexed: 12/22/2022]
Abstract
Liver transplantation is the ultimate treatment option for end-stage liver disease. Breakthroughs in surgical practice and immunosuppression have seen considerable advancements in survival after transplantation. However, the intricate management of immunosuppressive regimens, balancing desired immunological quiescence while minimizing toxicity has proven challenging. Diminishing improvements in long-term morbidity and mortality have been inextricably linked with the protracted use of these medications. As such, there is now enormous interest to devise protocols that will allow us to minimize or completely withdraw immunosuppressants after transplantation. Immunosuppression withdrawal trials have proved the reality of tolerance following liver transplantation, however, without intervention will only occur after several years at the risk of potential cumulative immunosuppression-related morbidity. Focus has now been directed at accelerating this phenomenon through tolerance-inducing strategies. In this regard, efforts have seen the use of regulatory cell immunotherapy. Here we focus particularly on regulatory T cells, discussing preclinical data that propagated several clinical trials of adoptive cell therapy in liver transplantation. Furthermore, we describe efforts to further optimize the specificity and survival of regulatory cell therapy guided by concurrent immunomonitoring studies and the development of novel technologies including chimeric antigen receptors and co-administration of low-dose IL-2.
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Affiliation(s)
- Niloufar Safinia
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Robert Ian Lechler
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
| | | | - Giovanna Lombardi
- Division of Transplantation Immunology & Mucosal BiologyKing's College LondonLondonUK
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31
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Yuan S, Chen Y, Zhang M, Wang Z, Hu Z, Ruan Y, Ren Z, Shi F. Overexpression of miR-223 Promotes Tolerogenic Properties of Dendritic Cells Involved in Heart Transplantation Tolerance by Targeting Irak1. Front Immunol 2021; 12:676337. [PMID: 34421892 PMCID: PMC8374072 DOI: 10.3389/fimmu.2021.676337] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 07/13/2021] [Indexed: 02/05/2023] Open
Abstract
Dendritic cells (DCs) are key mediators of transplant rejection. Numerous factors have been identified that regulate transplant immunopathology by modulating the function of DCs. Among these, microRNAs (miRNAs), small non-coding RNA molecules, have received much attention. The miRNA miR-223 is very highly expressed and tightly regulated in hematopoietic cells. It plays an important role in modulating the immune response by regulating neutrophils and macrophages, and its dysregulation contributes to multiple types of immune diseases. However, the role of miR-223 in immune rejection is unclear. Here, we observed expression of miR-223 in patients and mice who had undergone heart transplantation and found that it increased in the serum of both, and also in DCs from the spleens of recipient mice, although it was unchanged in splenic T cells. We also found that miR-223 expression decreased in lipopolysaccharide-stimulated DCs. Increasing the level of miR-223 in DCs promoted polarization of DCs toward a tolerogenic phenotype, which indicates that miR-223 can attenuate activation and maturation of DCs. MiR-223 effectively induced regulatory T cells (Tregs) by inhibiting the function of antigen-presenting DCs. In addition, we identified Irak1 as a miR-223 target gene and an essential regulator of DC maturation. In mouse allogeneic heterotopic heart transplantation models, grafts survived longer and suffered less immune cell infiltration in mice with miR-223-overexpressing immature (im)DCs. In the miR-223-overexpressing imDC recipients, T cells from spleen differentiated into Tregs, and the level of IL-10 in heart grafts was markedly higher than that in the control group. In conclusion, miR-223 regulates the function of DCs via Irak1, differentiation of T cells into Tregs, and secretion of IL-10, thereby suppressing allogeneic heart graft rejection.
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Affiliation(s)
- Shun Yuan
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuanyang Chen
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Min Zhang
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiwei Wang
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhipeng Hu
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yongle Ruan
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zongli Ren
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Shi
- Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Surgery Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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32
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Passeri L, Marta F, Bassi V, Gregori S. Tolerogenic Dendritic Cell-Based Approaches in Autoimmunity. Int J Mol Sci 2021; 22:8415. [PMID: 34445143 PMCID: PMC8395087 DOI: 10.3390/ijms22168415] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/02/2021] [Accepted: 08/03/2021] [Indexed: 12/15/2022] Open
Abstract
Dendritic cells (DCs) dictate the outcomes of tissue-specific immune responses. In the context of autoimmune diseases, DCs instruct T cells to respond to antigens (Ags), including self-Ags, leading to organ damage, or to becoming regulatory T cells (Tregs) promoting and perpetuating immune tolerance. DCs can acquire tolerogenic properties in vitro and in vivo in response to several stimuli, a feature that opens the possibility to generate or to target DCs to restore tolerance in autoimmune settings. We present an overview of the different subsets of human DCs and of the regulatory mechanisms associated with tolerogenic (tol)DC functions. We review the role of DCs in the induction of tissue-specific autoimmunity and the current approaches exploiting tolDC-based therapies or targeting DCs in vivo for the treatment of autoimmune diseases. Finally, we discuss limitations and propose future investigations for improving the knowledge on tolDCs for future clinical assessment to revert and prevent autoimmunity. The continuous expansion of tolDC research areas will lead to improving the understanding of the role that DCs play in the development and treatment of autoimmunity.
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Affiliation(s)
- Laura Passeri
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.P.); (F.M.); (V.B.)
- San Raffaele Scientific Institute IRCCS, University Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Fortunato Marta
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.P.); (F.M.); (V.B.)
| | - Virginia Bassi
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.P.); (F.M.); (V.B.)
- San Raffaele Scientific Institute IRCCS, University Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Silvia Gregori
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; (L.P.); (F.M.); (V.B.)
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33
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Kwon SP, Hwang BH, Park EH, Kim HY, Lee JR, Kang M, Song SY, Jung M, Sohn HS, Kim E, Kim CW, Lee KY, Oh GC, Choo E, Lim S, Chung Y, Chang K, Kim BS. Nanoparticle-Mediated Blocking of Excessive Inflammation for Prevention of Heart Failure Following Myocardial Infarction. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101207. [PMID: 34216428 DOI: 10.1002/smll.202101207] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/27/2021] [Indexed: 06/13/2023]
Abstract
Severe cardiac damage following myocardial infarction (MI) causes excessive inflammation, which sustains tissue damage and often induces adverse cardiac remodeling toward cardiac function impairment and heart failure. Timely resolution of post-MI inflammation may prevent cardiac remodeling and development of heart failure. Cell therapy approaches for MI are time-consuming and costly, and have shown marginal efficacy in clinical trials. Here, nanoparticles targeting the immune system to attenuate excessive inflammation in infarcted myocardium are presented. Liposomal nanoparticles loaded with MI antigens and rapamycin (L-Ag/R) enable effective induction of tolerogenic dendritic cells presenting the antigens and subsequent induction of antigen-specific regulatory T cells (Tregs). Impressively, intradermal injection of L-Ag/R into acute MI mice attenuates inflammation in the myocardium by inducing Tregs and an inflammatory-to-reparative macrophage polarization, inhibits adverse cardiac remodeling, and improves cardiac function. Nanoparticle-mediated blocking of excessive inflammation in infarcted myocardium may be an effective intervention to prevent the development of post-MI heart failure.
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Affiliation(s)
- Sung Pil Kwon
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Hee Hwang
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Eun-Hye Park
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Han Young Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Ju-Ro Lee
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Mikyung Kang
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seuk Young Song
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Mungyo Jung
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Hee Su Sohn
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Eunmin Kim
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Chan Woo Kim
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Kwan Yong Lee
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Gyu Chul Oh
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Eunho Choo
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Songhyun Lim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Kiyuk Chang
- Cardiovascular Research Institute for Intractable Disease, Division of Cardiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea
- Interdisciplinary Program for Bioengineering, Seoul National University, Seoul, 08826, Republic of Korea
- Institute of Chemical Processes, Institute of Engineering Research, BioMAX, Seoul National University, Seoul, 08826, Republic of Korea
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34
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Suuring M, Moreau A. Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies. Int J Mol Sci 2021; 22:7970. [PMID: 34360736 PMCID: PMC8348814 DOI: 10.3390/ijms22157970] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn's disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.
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Affiliation(s)
| | - Aurélie Moreau
- Centre de Recherche en Transplantation et Immunologie—UMR1064, INSERM—ITUN, Nantes Université, CHU Nantes, 44000 Nantes, France;
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35
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Preclinical Assessment of Autologous Tolerogenic Dendritic Cells From End-stage Renal Disease Patients. Transplantation 2021; 105:832-841. [PMID: 32433241 DOI: 10.1097/tp.0000000000003315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Kidney transplantation is the therapeutic of choice for patients with kidney failure. While immunosuppressive drugs can control graft rejection, their use is associated with increased infections and cancer, and they do not effectively control chronic graft rejection. Cell therapy is an attractive strategy to minimize the use of pharmacological drugs. METHODS We recently developed a protocol to generate human monocyte-derived autologous tolerogenic dendritic cells (ATDCs) from healthy volunteers. Herein, we transferred the ATDC manufacturing protocol to a Good Manufacturing Practice (GMP)-compliant facility. Furthermore, we compared the phenotype and in vitro functions of ATDCs generated from patients with end-stage renal disease to those generated from healthy volunteers. RESULTS We describe the critical steps for GMP-compliant production of ATDCs and define the quality criteria required to allow release of the cell products. Furthermore, we showed that ATDCs generated from healthy volunteers and patients with kidney failure display the same tolerogenic profile based on their phenotype, resistance to maturation, and ability to modulate T-cell responses. CONCLUSIONS Together, these results allowed us to define the production process and the quality criteria for the release of ATDCs before their administration in patients receiving a kidney transplant.
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36
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Zhang X, Liu D, He M, Lin M, Tu C, Zhang B. Polymeric nanoparticles containing rapamycin and autoantigen induce antigen-specific immunological tolerance for preventing vitiligo in mice. Hum Vaccin Immunother 2021; 17:1923-1929. [PMID: 33616474 DOI: 10.1080/21645515.2021.1872342] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Vitiligo is an autoimmune disease in which pigment is lost in patches of the skin. CD4+ T cells are implicated in vitiligo while regulatory T cells (Tregs) could ameliorate vitiligo. Rapamycin together with autoantigen have been shown to induce immunological tolerance and promote Tregs in multiple autoimmune diseases. In the current study, we synthesized nanoparticles containing rapamycin and autoantigen HEL46-61 (NPHEL46-61/Rapa) and investigated their effects on vitiligo. We treated bone marrow-derived dendritic cells (BMDCs) from TrpHEL mice with NPHEL46-61/Rapa and monitored the phenotype of BMDCs. We investigated the effects of NPHEL46-61/Rapa-treated BMDCs on CD4+ T cell proliferation and differentiation. We administrated NPHEL46-61/Rapa to TCR-TrpHEL mice and investigated the effects on vitiligo. We found that BMDCs can uptake the NPHEL46-61/Rapa, which resulted in decreased expression of costimulation molecules CD80 and CD86 in BMDCs. BMDCs treated with NPHEL46-61/Rapa suppressed antigen-specific CD4+ T cell proliferation while promoted the differentiation of these CD4+ T cell to Tregs in vitro. Administration of NPHEL46-61/Rapa to TCR-TrpHEL mice ameliorated vitiligo, promoted Treg production, and suppressed IFN-γ and IL-6 production, while induced IL-10 production. Therefore, our study provides experimental evidence that nanoparticles containing rapamycin and autoantigen could induce antigen-specific immunological tolerance and prevent vitiligo.
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Affiliation(s)
- Xia Zhang
- Department of Dermatology, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
| | - Daji Liu
- Department of Rheumatology, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
| | - Minghong He
- Department of Respiratory Medicine, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
| | - Mao Lin
- Department of Dermatology, Chongqing Chinese Medicine Hospital, Chongqing, China
| | - Caixia Tu
- Department of Dermatology, The 2nd Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Baoxiang Zhang
- Department of Dermatology, Weifang Yidu Central Hospital, Qingzhou, Shandong, China
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37
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Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury. Int J Mol Sci 2021; 22:ijms22105386. [PMID: 34065421 PMCID: PMC8160749 DOI: 10.3390/ijms22105386] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/13/2021] [Accepted: 05/17/2021] [Indexed: 02/07/2023] Open
Abstract
Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.
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38
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Lin J, Wang H, Liu C, Cheng A, Deng Q, Zhu H, Chen J. Dendritic Cells: Versatile Players in Renal Transplantation. Front Immunol 2021; 12:654540. [PMID: 34093544 PMCID: PMC8170486 DOI: 10.3389/fimmu.2021.654540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 04/22/2021] [Indexed: 12/30/2022] Open
Abstract
Dendritic cells (DCs) induce and regulate adaptive immunity through migrating and maturing in the kidney. In this procedure, they can adopt different phenotypes—rejection-associated DCs promote acute or chronic injury renal grafts while tolerogenic DCs suppress the overwhelmed inflammation preventing damage to renal functionality. All the subsets interact with effector T cells and regulatory T cells (Tregs) stimulated by the ischemia–reperfusion procedure, although the classification corresponding to different effects remains controversial. Thus, in this review, we discuss the origin, maturation, and pathological effects of DCs in the kidney. Then we summarize the roles of divergent DCs in renal transplantation: taking both positive and negative stages in ischemia–reperfusion injury (IRI), switching phenotypes to induce acute or chronic rejection, and orchestrating surface markers for allograft tolerance via alterations in metabolism. In conclusion, we prospect that multidimensional transcriptomic analysis will revolute researches on renal transplantation by addressing the elusive mononuclear phagocyte classification and providing a holistic view of DC ontogeny and subpopulations.
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Affiliation(s)
- Jinwen Lin
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Disease, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
| | - Hongyi Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Chenxi Liu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Ao Cheng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Qingwei Deng
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Huijuan Zhu
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Kidney Disease Prevention and Control Technology, National Key Clinical Department of Kidney Disease, Institute of Nephrology, Zhejiang University, Hangzhou, China.,The Third Grade Laboratory under the National State, Administration of Traditional Chinese Medicine, Hangzhou, China
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Rahimi K, Hassanzadeh K, Khanbabaei H, Haftcheshmeh SM, Ahmadi A, Izadpanah E, Mohammadi A, Sahebkar A. Curcumin: A Dietary Phytochemical for Targeting the Phenotype and Function of Dendritic Cells. Curr Med Chem 2021; 28:1549-1564. [PMID: 32410550 DOI: 10.2174/0929867327666200515101228] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 04/05/2020] [Accepted: 04/19/2020] [Indexed: 11/22/2022]
Abstract
Dendritic cells (DCs) are the most powerful antigen-presenting cells which link the innate and adaptive immune responses. Depending on the context, DCs initiate the immune responses or contribute to immune tolerance. Any disturbance in their phenotypes and functions may initiate inflammatory or autoimmune diseases. Hence, dysregulated DCs are the most attractive pharmacological target for the development of new therapies aiming at reducing their immunogenicity and at enhancing their tolerogenicity. Curcumin is the polyphenolic phytochemical component of the spice turmeric with a wide range of pharmacological activities. It acts in several ways as a modulator of DCs and converts them into tolerogenic DCs. Tolerogenic DCs possess anti-inflammatory and immunomodulatory activities that regulate the immune responses in health and disease. Curcumin by blocking maturation markers, cytokines and chemokines expression, and disrupting the antigen-presenting machinery of DCs render them non- or hypo-responsive to immunostimulants. It also reduces the expression of co-stimulatory and adhesion molecules on DCs and prevents them from both migration and antigen presentation but enhances their endocytosis capacity. Hence, curcumin causes DCs-inducing regulatory T cells and dampens CD4+ T helper 1 (Th1), Th2, and Th17 polarization. Inhibition of transcription factors such as NF-κB, AP-1, MAPKs (p38, JNK, ERK) and other intracellular signaling molecules such as JAK/STAT/SOCS provide a plausible explanation for most of these observations. In this review, we summarize the potential effects of curcumin on the phenotypes and functions of DCs as the key players in orchestration, stimulation, and modulation of the immune responses.
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Affiliation(s)
- Kaveh Rahimi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Kambiz Hassanzadeh
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Hashem Khanbabaei
- Medical Physics Department, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Saeed M Haftcheshmeh
- Department of Medical Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91766-99199, Iran
| | - Abbas Ahmadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Esmael Izadpanah
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Asadollah Mohammadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
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Kalinina O, Talley S, Zamora-Pineda J, Paik W, Campbell EM, Knight KL. Amelioration of Graft-versus-Host Disease by Exopolysaccharide from a Commensal Bacterium. THE JOURNAL OF IMMUNOLOGY 2021; 206:2101-2108. [PMID: 33846225 DOI: 10.4049/jimmunol.2000780] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 03/02/2021] [Indexed: 01/07/2023]
Abstract
Acute graft-versus-host disease (aGvHD) is a severe, often lethal, complication of hematopoietic stem cell transplantation, and although prophylactic regimens are given as standard pretransplantation therapy, up to 60% of these patients develop aGvHD, and require additional immunosuppressive intervention. We treated mice with a purified probiotic molecule, exopolysaccharide (EPS) from Bacillus subtilis, shortly before and after induction of aGvHD and found that, whereas only 10% of control mice survived to day 80, 70% of EPS-treated mice survived to 80 d. EPS treatment of donor-only mice resulted in ∼60% survival. Using a biosensor mouse model to assess inflammation in live mice during aGvHD, we found that EPS prevented the activation of alloreactive donor T cells. In vitro, EPS did not affect T cells directly but, instead, induced bone marrow-derived dendritic cells (BMDCs) that displayed characteristics of inhibitory dendritic cells (DCs). Development of these BMDCs required TLR4 signaling through both MyD88 and TRIF pathways. Using BMDCs derived from IDO knockout mice, we showed that T cell inhibition by EPS-treated BMDCs was mediated through the suppressive effects of IDO. These studies describe a bacterial molecule that modulates immune responses by inducing inhibitory DCs in a TLR4-dependent manner, and these cells have the capacity to inhibit T cell activation through IDO. We suggest that EPS or EPS-treated DCs can serve as novel agents for preventing aGvHD.
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Affiliation(s)
- Olga Kalinina
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Sarah Talley
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Jesus Zamora-Pineda
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Wonbeom Paik
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Edward M Campbell
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
| | - Katherine L Knight
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL
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Liu Q, Wang X, Liu X, Liao YP, Chang CH, Mei KC, Jiang J, Tseng S, Gochman G, Huang M, Thatcher Z, Li J, Allen SD, Lucido L, Xia T, Nel AE. Antigen- and Epitope-Delivering Nanoparticles Targeting Liver Induce Comparable Immunotolerance in Allergic Airway Disease and Anaphylaxis as Nanoparticle-Delivering Pharmaceuticals. ACS NANO 2021; 15:1608-1626. [PMID: 33351586 PMCID: PMC7943028 DOI: 10.1021/acsnano.0c09206] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
The targeting of natural tolerogenic liver sinusoidal endothelial cells (LSEC) by nanoparticles (NPs), decorated with a stabilin receptor ligand, is capable of generating regulatory T-cells (Tregs), which can suppress antigen-specific immune responses, including to ovalbumin (OVA), a possible food allergen. In this regard, we have previously demonstrated that OVA-encapsulating poly(lactic-co-glycolic acid) (PLGA) nanoparticles eliminate allergic airway inflammation in OVA-sensitized mice, prophylactically and therapeutically. A competing approach is a nanocarrier platform that incorporates pharmaceutical agents interfering in mTOR (rapamycin) or NF-κB (curcumin) pathways, with the ability to induce a tolerogenic state in nontargeted antigen-presenting cells system-wide. First, we compared OVA-encapsulating, LSEC-targeting tolerogenic nanoparticles (TNPs) with nontargeted NPs incorporating curcumin and rapamycin (Rapa) in a murine eosinophilic airway inflammation model, which is Treg-sensitive. This demonstrated roughly similar tolerogenic effects on allergic airway inflammation by stabilin-targeting NPOVAversus nontargeted NPs delivering OVA plus Rapa. Reduction in eosinophilic inflammation and TH2-mediated immune responses in the lung was accompanied by increased Foxp3+ Treg recruitment and TGF-β production in both platforms. As OVA incorporates IgE-binding as well as non-IgE-binding epitopes, the next experiment explored the possibility of obtaining immune tolerance by non-anaphylactic T-cell epitopes. This was accomplished by incorporating OVA323-339 and OVA257-264 epitopes in liver-targeting NPs to assess the prophylactic and therapeutic impact on allergic inflammation in transgenic OT-II mice. Importantly, we demonstrated that the major histocompatibility complex (MHC)-II binding (former) but not the MHC-I binding (latter) epitope interfered in allergic airway inflammation, improving TNPOVA efficacy. The epitope-specific effect was transduced by TGF-β-producing Tregs. In the final phase of experimentation, we used an OVA-induced anaphylaxis model to demonstrate that targeted delivery of OVA and its MHC-II epitope could significantly suppress the anaphylaxis symptom score, mast cell release, and the late-phase inflammatory response. In summary, these results demonstrate comparable efficacy of LSEC-targeting versus pharmaceutical PLGA nanoparticles, as well as the ability of T-cell epitopes to achieve response outcomes similar to those of the intact allergens.
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Affiliation(s)
- Qi Liu
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Xiang Wang
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Xiangsheng Liu
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Yu-Pei Liao
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Chong Hyun Chang
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Kuo-Ching Mei
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Jinhong Jiang
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Shannon Tseng
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Grant Gochman
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Marissa Huang
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Zoe Thatcher
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Jiulong Li
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Sean D. Allen
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Luke Lucido
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
| | - Tian Xia
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, CA 90095, USA
- Corresponding author ;
| | - Andre E. Nel
- Center of Environmental Implications of Nanotechnology (UC CEIN), University of California, Los Angeles, CA 90095, USA
- California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA
- Division of NanoMedicine, Department of Medicine, University of California, Los Angeles, CA 90095, USA
- Corresponding author ;
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López-Abente J, Martínez-Bonet M, Bernaldo-de-Quirós E, Camino M, Gil N, Panadero E, Gil-Jaurena JM, Clemente M, Urschel S, West L, Pion M, Correa-Rocha R. Basiliximab impairs regulatory T cell (TREG) function and could affect the short-term graft acceptance in children with heart transplantation. Sci Rep 2021; 11:827. [PMID: 33436905 PMCID: PMC7803770 DOI: 10.1038/s41598-020-80567-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 12/21/2020] [Indexed: 12/26/2022] Open
Abstract
CD25, the alpha chain of the IL-2 receptor, is expressed on activated effector T cells that mediate immune graft damage. Induction immunosuppression is commonly used in solid organ transplantation and can include antibodies blocking CD25. However, regulatory T cells (Tregs) also rely on CD25 for their proliferation, survival, and regulatory function. Therefore, CD25-blockade may compromise Treg protective role against rejection. We analysed in vitro the effect of basiliximab (BXM) on the viability, phenotype, proliferation and cytokine production of Treg cells. We also evaluated in vivo the effect of BXM on Treg in thymectomized heart transplant children receiving BXM in comparison to patients not receiving induction therapy. Our results show that BXM reduces Treg counts and function in vitro by affecting their proliferation, Foxp3 expression, and IL-10 secretion capacity. In pediatric heart-transplant patients, we observed decreased Treg counts and a diminished Treg/Teff ratio in BXM-treated patients up to 6-month after treatment, recovering baseline values at the end of the 12-month follow up period. These results reveal that the use of BXM could produce detrimental effects on Tregs, and support the evidence suggesting that BXM induction could impair the protective role of Tregs in the period of highest incidence of acute graft rejection.
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Affiliation(s)
- Jacobo López-Abente
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Pabellón de Medicina Experimental, Planta Baja. C/ Maiquez, 6., 28006, Madrid, Spain
| | - Marta Martínez-Bonet
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Pabellón de Medicina Experimental, Planta Baja. C/ Maiquez, 6., 28006, Madrid, Spain
| | - Esther Bernaldo-de-Quirós
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Pabellón de Medicina Experimental, Planta Baja. C/ Maiquez, 6., 28006, Madrid, Spain
| | - Manuela Camino
- Pediatric-Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Nuria Gil
- Pediatric-Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Esther Panadero
- Pediatric-Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Juan Miguel Gil-Jaurena
- Pediatric Cardiac Surgery Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Maribel Clemente
- Cell Culture Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Simon Urschel
- Pediatric Cardiac Transplantation, University of Alberta/Stollery Children's Hospital, Edmonton, AB, Canada.,Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.,Canadian National Transplant Research Program Investigator, CNTRP, Edmonton, AB, Canada
| | - Lori West
- Pediatric Cardiac Transplantation, University of Alberta/Stollery Children's Hospital, Edmonton, AB, Canada.,Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.,Canadian National Transplant Research Program Investigator, CNTRP, Edmonton, AB, Canada
| | - Marjorie Pion
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Pabellón de Medicina Experimental, Planta Baja. C/ Maiquez, 6., 28006, Madrid, Spain
| | - Rafael Correa-Rocha
- Laboratory of Immune-Regulation, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Pabellón de Medicina Experimental, Planta Baja. C/ Maiquez, 6., 28006, Madrid, Spain. .,Canadian National Transplant Research Program Investigator, CNTRP, Edmonton, AB, Canada.
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Trujillo-Vargas CM, Kutlehria S, Hernandez H, de Souza RG, Lee A, Yu Z, Pflugfelder SC, Singh M, de Paiva CS. Rapamycin Eyedrops Increased CD4 +Foxp3 + Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface. Int J Mol Sci 2020; 21:ijms21238890. [PMID: 33255287 PMCID: PMC7727717 DOI: 10.3390/ijms21238890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/12/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022] Open
Abstract
Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident (IFN-γ, IL-12, CIITA and Ctss); this was accompanied by slightly diminished Unc-51 Like Autophagy Activating Kinase 1 (ULK1) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45+CD4+Foxp3+ cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.
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Affiliation(s)
- Claudia M. Trujillo-Vargas
- Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellín 050010, Colombia;
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (H.H.); (R.G.d.S.); (Z.Y.); (S.C.P.)
| | - Shallu Kutlehria
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (S.K.); (M.S.)
| | - Humberto Hernandez
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (H.H.); (R.G.d.S.); (Z.Y.); (S.C.P.)
| | - Rodrigo G. de Souza
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (H.H.); (R.G.d.S.); (Z.Y.); (S.C.P.)
| | - Andrea Lee
- Graduate Program in Immunology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Zhiyuan Yu
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (H.H.); (R.G.d.S.); (Z.Y.); (S.C.P.)
| | - Stephen C. Pflugfelder
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (H.H.); (R.G.d.S.); (Z.Y.); (S.C.P.)
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA; (S.K.); (M.S.)
| | - Cintia S. de Paiva
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA; (H.H.); (R.G.d.S.); (Z.Y.); (S.C.P.)
- Correspondence: ; Tel.: +1-713-798-2124
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Modulatory effect of rapamycin and tacrolimus on monocyte-derived dendritic cells phenotype and function. Immunobiology 2020; 226:152031. [PMID: 33278711 DOI: 10.1016/j.imbio.2020.152031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 10/16/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive-drugs are needed after solid organ transplantation to prevent allograft rejection but induce severe side effects. Understanding the alloimmune response is critical to modulate it and to achieve graft operational tolerance. The role of regulatory T cells and tolerogenic dendritic cells (Tol-DCs) is undoubtedly essential in tolerance induction. Tacrolimus is considered as the cornerstone of immunosuppression in solid organ transplantation. mTOR inhibitor such as rapamycin are thought to induce tolerance and are used as anticancer drugs in several cancers. The aim of this study was to better understand the effect of these immunosuppressive drugs on the differentiation, maturation and function of human monocyte derived dendritic cells (DCs). MATERIAL AND METHODS DCs were differentiated from monocytes of healthy donors with either rapamycin (Rapa-DCs) or tacrolimus (Tac-DCs). The phenotype was evaluated by flow cytometry analysis. The production of pro- and anti-inflammatory cytokines was assessed by ELISA. The mRNA expression level of IDO and PD-L1 was assessed by RTqPCR. Mixed leukocytes reactions were performed to analyse suppressive activity of DCs. RESULTS Rapa-DC were characterised by a lower expression of the co-stimulatory molecules and CD83 than control-DCs (CTR-DC) (p < 0.05). In contrast, tacrolimus had no effect on the expression of surface markers compared to CTR-DCs. Rapamycin reduced both IL-12 and IL-10 secretions (p < 0.05). Rapa-DCs had a suppressive effect on CD4+ allogenic T cells compared to CTR-DCs (p < 0.05). However, neither Rapa-DCs nor Tac-DCs favoured the emergence of a CD4+CD25highFoxp3+ population compared to CTR-DCs. Surprisingly, Rapa-DCs had a reduced expression of IDO and PD-L1 compared to Tac-DCs and CTR-DCs. CONCLUSION Rapa-DCs exhibit an incomplete phenotypic tolerogenic profile. To our knowledge this is the first paper showing a reduction of expression of pro-tolerogenic enzyme IDO in DCs. Tacrolimus does not change the phenotypical or functional characteristics of moDCs.
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Immune and gene expression profiling during tacrolimus to everolimus conversion early after liver transplantation. Hum Immunol 2020; 82:81-88. [PMID: 33213941 DOI: 10.1016/j.humimm.2020.10.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/25/2020] [Accepted: 10/31/2020] [Indexed: 01/08/2023]
Abstract
Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver transplant. Blood samples were collected at month 3 (withdrawal initiation), 4 (withdrawal completion), 4.5 and 6 (both everolimus alone). 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption. Before tacrolimus withdrawal, eventual rejecters had higher percentages of CD56+ NK cells and CD19+CD27+CD24+ memory B cells, and lower levels of T cells expressing the exhaustion marker PD-1. Over time, memory B cells, Ki-67+CD3+ (proliferating) cells and CD4+CD127-CD25HIGH FOXP3+ Tregs increased in rejecters. Tregs also increased in non-rejecters over time. The number of differentially expressed genes progressively increased in rejecters, particularly in mTOR, Eukaryotic Initiation Factor 2, and Neuroinflammation signaling pathways. There was no difference in anti-HLA antibodies between the groups. In summary, blood mononuclear cell and gene expression may predict successful vs. failed early tacrolimus withdrawal in liver transplant recipients. While needing validation, these preliminary findings highlight the potential for cellular and molecular biomarkers to guide decision-making during tacrolimus weaning.
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Park HW, Park SH, Jo HJ, Kim TG, Lee JH, Kang SG, Jang YS, Kim PH. Lactoferrin Induces Tolerogenic Bone Marrow-Derived Dendritic Cells. Immune Netw 2020; 20:e38. [PMID: 33163246 PMCID: PMC7609161 DOI: 10.4110/in.2020.20.e38] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/03/2022] Open
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that initiate both T-cell responses and tolerance. Tolerogenic DCs (tDCs) are regulatory DCs that suppress immune responses through the induction of T-cell anergy and Tregs. Because lactoferrin (LF) was demonstrated to induce functional Tregs and has a protective effect against inflammatory bowel disease, we explored the tolerogenic effects of LF on mouse bone marrow-derived DCs (BMDCs). The expression of CD80/86 and MHC class II was diminished in LF-treated BMDCs (LF-BMDCs). LF facilitated BMDCs to suppress proliferation and elevate Foxp3+ induced Treg (iTreg) differentiation in ovalbumin-specific CD4+ T-cell culture. Foxp3 expression was further increased by blockade of the B7 molecule using CTLA4-Ig but was diminished by additional CD28 stimulation using anti-CD28 Ab. On the other hand, the levels of arginase-1 and indoleamine 2,3-dioxygenase-1 (known as key T-cell suppressive molecules) were increased in LF-BMDCs. Consistently, the suppressive activity of LF-BMDCs was partially restored by inhibitors of these molecules. Collectively, these results suggest that LF effectively causes DCs to be tolerogenic by both the suppression of T-cell proliferation and enhancement of iTreg differentiation. This tolerogenic effect of LF is due to the reduction of costimulatory molecules and enhancement of suppressive molecules.
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Affiliation(s)
- Hui-Won Park
- Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Sun-Hee Park
- Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Hyeon-Ju Jo
- Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Tae-Gyu Kim
- Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Jeong Hyun Lee
- Department of Systems Immunology, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Seung-Goo Kang
- Department of Systems Immunology, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Young-Saeng Jang
- Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Korea.,Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
| | - Pyeung-Hyeun Kim
- Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, Korea.,Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University, Chuncheon, Korea
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Que W, Guo WZ, Li XK. Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance. Front Immunol 2020; 11:582658. [PMID: 33162996 PMCID: PMC7591396 DOI: 10.3389/fimmu.2020.582658] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/31/2020] [Indexed: 12/13/2022] Open
Abstract
Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.
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Affiliation(s)
- Weitao Que
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Wen-Zhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao-Kang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
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Zhuang Q, Cai H, Cao Q, Li Z, Liu S, Ming Y. Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation. Front Immunol 2020; 11:552988. [PMID: 33123131 PMCID: PMC7573100 DOI: 10.3389/fimmu.2020.552988] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/12/2020] [Indexed: 12/19/2022] Open
Abstract
Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.
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Affiliation(s)
- Quan Zhuang
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Haozheng Cai
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China
| | - Qingtai Cao
- Hunan Normal University School of Medicine, Changsha, China
| | - Zixin Li
- Hunan Normal University School of Medicine, Changsha, China
| | - Shu Liu
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
| | - Yingzi Ming
- Transplantation Center of the 3rd Xiangya Hospital, Central South University, Changsha, China.,Research Center of National Health Ministry on Transplantation Medicine, Changsha, China
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Emoto S, Shibasaki S, Nagatsu A, Goto R, Ono H, Fukasaku Y, Igarashi R, Ota T, Fukai M, Shimamura T, Saiga K, Taketomi A, Murakami M, Todo S, Yamashita K. Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4 +CD25 +Foxp3 + T cells and ameliorates allograft rejection in an antigen-specific manner. Transpl Immunol 2020; 65:101338. [PMID: 33022372 DOI: 10.1016/j.trim.2020.101338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 10/02/2020] [Accepted: 10/02/2020] [Indexed: 11/19/2022]
Abstract
We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST). BALB/c (H-2d) heart graft were transplanted into C57BL/6 (H-2b) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2k). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8+ T cells in the spleen and inhibited infiltration of CD8+ T cells into the graft. Depletion of CD25+ cells inhibited the graft prolonging effect of the NK026680 plus DST treatment. NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs.
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Affiliation(s)
- Shin Emoto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Susumu Shibasaki
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Akihisa Nagatsu
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Hitoshi Ono
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Yasutomo Fukasaku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Rumi Igarashi
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Takuji Ota
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Moto Fukai
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan.
| | - Kan Saiga
- Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Masaaki Murakami
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
| | - Satoru Todo
- Research Institute of St. Mary's Hospital, Kurume, Japan.
| | - Kenichiro Yamashita
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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50
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Yang C, Ge J, Rosales I, Yuan Q, Szuter E, Acheampong E, Russell PS, Madsen JC, Colvin RB, Alessandrini A. Kidney-induced systemic tolerance of heart allografts in mice. JCI Insight 2020; 5:139331. [PMID: 32938831 PMCID: PMC7526548 DOI: 10.1172/jci.insight.139331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 08/14/2020] [Indexed: 01/10/2023] Open
Abstract
In swine and nonhuman primates, kidney allografts can induce tolerance of heart allografts, leading to their long-term, immunosuppression-free survival. We refer to this phenomenon as kidney-induced cardiac allograft tolerance (KICAT). In this study, we have developed a murine model for KICAT to determine the underlining cellular/molecular mechanisms. Here, we show that spontaneously accepted DBA/2J kidneys in C57BL/6 recipients induce systemic tolerance that results in the long-term acceptance of DBA/2J heart allografts but not third-party cardiac allografts. The state of systemic tolerance of hearts was established 2 weeks after transplantation of the kidney, after which time, the kidney allograft is no longer required. Depletion of Foxp3+ T cells from these mice precipitated rejection of the heart allografts, indicating that KICAT is dependent on Treg function. Acceptance of kidney allografts and cotransplanted heart allografts did not require the thymus. In conclusion, these data show that kidney allografts induce systemic, donor-specific tolerance of cardiac allografts via Foxp3 cells, and that tolerance is independent of the thymus and continued presence of the kidney allograft. This experimental system should promote increased understanding of the tolerogenic mechanisms of the kidney. Accepted DBA/2J kidney allografts can confer acceptance of a co-transplanted DBA/2 heart allograft, which would be rejected when transplanted in the absence of the kidney graft.
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Affiliation(s)
- Chao Yang
- Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.,Center for Transplantation Sciences, Department of Surgery, and.,Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Jifu Ge
- Center for Transplantation Sciences, Department of Surgery, and.,Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Ivy Rosales
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Qing Yuan
- Center for Transplantation Sciences, Department of Surgery, and.,Organ Transplant Institute, 8th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Edward Szuter
- Center for Transplantation Sciences, Department of Surgery, and
| | - Ellen Acheampong
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Paul S Russell
- Center for Transplantation Sciences, Department of Surgery, and
| | - Joren C Madsen
- Center for Transplantation Sciences, Department of Surgery, and.,Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Robert B Colvin
- Center for Transplantation Sciences, Department of Surgery, and.,Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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