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Annamalai C, Kute V, Sheridan C, Halawa A. Hematopoietic cell-based and non-hematopoietic cell-based strategies for immune tolerance induction in living-donor renal transplantation: A systematic review. Transplant Rev (Orlando) 2023; 37:100792. [PMID: 37709652 DOI: 10.1016/j.trre.2023.100792] [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: 12/30/2022] [Revised: 04/24/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023]
Abstract
INTRODUCTION Despite its use to prevent acute rejection, lifelong immunosuppression can adversely impact long-term patient and graft outcomes. In theory, immunosuppression withdrawal is the ultimate goal of kidney transplantation, and is made possible by the induction of immunological tolerance. The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism-based and non-chimerism-based. The impact of these strategies on transplant outcomes, including acute rejection, allograft function and survival, cost, and immune monitoring, will also be discussed. MATERIALS AND METHODS Databases such as PubMed, Scopus, and Web of Science, as well as additional online resources such as EBSCO, were exhaustively searched. Adult living-donor kidney transplant recipients who developed chimerism-based tolerance after concurrent bone marrow or hematopoietic stem cell transplantation or those who received non-chimerism-based, non-hematopoietic cell therapy using mesenchymal stromal cells, dendritic cells, or regulatory T cells were studied between 2000 and 2021. Individual sources of evidence were evaluated critically, and the strength of evidence and risk of bias for each outcome of the transplant tolerance study were assessed. RESULTS From 28,173 citations, 245 studies were retrieved after suitable exclusion and duplicate removal. Of these, 22 studies (2 RCTs, 11 cohort studies, 6 case-control studies, and 3 case reports) explicitly related to both interventions (chimerism- and non-chimerism-based immune tolerance) were used in the final review process and were critically appraised. According to the findings, chimerism-based strategies fostered immunotolerance, allowing for the safe withdrawal of immunosuppressive medications. Cell-based therapy, on the other hand, frequently did not induce tolerance except for minimising immunosuppression. As a result, the rejection rates, renal allograft function, and survival rates could not be directly compared between these two groups. While chimerism-based tolerance protocols posed safety concerns due to myelosuppression, including infections and graft-versus-host disease, cell-based strategies lacked these adverse effects and were largely safe. There was a lack of direct comparisons between HLA-identical and HLA-disparate recipients, and the cost implications were not examined in several of the retrieved studies. Most studies reported successful immunosuppressive weaning lasting at least 3 years (ranging up to 11.4 years in some studies), particularly with chimerism-based therapy, while only a few investigators used immune surveillance techniques. The studies reviewed were often limited by selection, classification, ascertainment, performance, and attrition bias. CONCLUSIONS This review demonstrates that chimerism-based hematopoietic strategies induce immune tolerance, and a substantial number of patients are successfully weaned off immunosuppression. Despite the risk of complications associated with myelosuppression. Non-chimerism-based, non-hematopoietic cell protocols, on the other hand, have been proven to facilitate immunosuppression minimization but seldom elicit immunological tolerance. However, the results of this review must be interpreted with caution because of the non-randomised study design, potential confounding, and small sample size of the included studies. Further validation and refinement of tolerogenic protocols in accordance with local practice preferences is also warranted, with an emphasis on patient selection, cost ramifications, and immunological surveillance based on reliable tolerance assays.
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Affiliation(s)
- Chandrashekar Annamalai
- Postgraduate School of Medicine, Institute of Teaching and Learning, Faculty of Health and Life Sciences, University of Liverpool, UK.
| | - Vivek Kute
- Nephrology and Transplantation, Institute of Kidney Diseases and Research Center and Dr. H L Trivedi Institute of Transplantation Sciences (IKDRC-ITS), Ahmedabad, India
| | - Carl Sheridan
- Department of Eye and Vision Science, Ocular Cell Transplantation, Faculty of Health and Life Sciences, University of Liverpool, UK
| | - Ahmed Halawa
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Farhana S, Kai YC, Kadir R, Sulaiman WAW, Nordin NA, Nasir NAM. The fate of adipose tissue and adipose-derived stem cells in allograft. Cell Tissue Res 2023; 394:269-292. [PMID: 37624425 DOI: 10.1007/s00441-023-03827-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/15/2023] [Indexed: 08/26/2023]
Abstract
Utilizing adipose tissue and adipose-derived stem cells (ADSCs) turned into a promising field of allograft in recent years. The therapeutic potential of adipose tissue and ADSCs is governed by their molecular secretions, ability to sustain multi-differentiation and self-renewal which are pivotal in reconstructive, genetic diseases, and cosmetic goals. However, revisiting the existing functional capacity of adipose tissue and ADSCs and their intricate relationship with allograft is crucial to figure out the remarkable question of safety to use in allograft due to the growing evidence of interactions between tumor microenvironment and ADSCs. For instance, the molecular secretions of adipose tissue and ADSCs induce angiogenesis, create growth factors, and control the inflammatory response; it has now been well determined. Though the existing preclinical allograft studies gave positive feedback, ADSCs and adipose tissue are attracted by some factors of tumor stroma. Moreover, allorecognition is pivotal to allograft rejection which is carried out by costimulation in a complement-dependent way and leads to the destruction of the donor cells. However, extensive preclinical trials of adipose tissue and ADSCs in allograft at molecular level are still limited. Hence, comprehensive immunomodulatory analysis could ensure the successful allograft of adipose tissue and ADSCs avoiding the oncological risk.
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Affiliation(s)
- Sadia Farhana
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Yew Chun Kai
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Ramlah Kadir
- Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Wan Azman Wan Sulaiman
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Nor Asyikin Nordin
- Department of Immunology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia
| | - Nur Azida Mohd Nasir
- Reconstructive Sciences Unit, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, 16150, Kota Bharu, Kelantan, Malaysia.
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Cheung J, Zahorowska B, Suranyi M, Wong JKW, Diep J, Spicer ST, Verma ND, Hodgkinson SJ, Hall BM. CD4 +CD25 + T regulatory cells in renal transplantation. Front Immunol 2022; 13:1017683. [PMID: 36426347 PMCID: PMC9681496 DOI: 10.3389/fimmu.2022.1017683] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/13/2022] [Indexed: 09/14/2023] Open
Abstract
The immune response to an allograft activates lymphocytes with the capacity to cause rejection. Activation of CD4+CD25+Foxp3+T regulatory cells (Treg) can down-regulate allograft rejection and can induce immune tolerance to the allograft. Treg represent <10% of peripheral CD4+T cells and do not markedly increase in tolerant hosts. CD4+CD25+Foxp3+T cells include both resting and activated Treg that can be distinguished by several markers, many of which are also expressed by effector T cells. More detailed characterization of Treg to identify increased activated antigen-specific Treg may allow reduction of non-specific immunosuppression. Natural thymus derived resting Treg (tTreg) are CD4+CD25+Foxp3+T cells and only partially inhibit alloantigen presenting cell activation of effector cells. Cytokines produced by activated effector cells activate these tTreg to more potent alloantigen-activated Treg that may promote a state of operational tolerance. Activated Treg can be distinguished by several molecules they are induced to express, or whose expression they have suppressed. These include CD45RA/RO, cytokine receptors, chemokine receptors that alter pathways of migration and transcription factors, cytokines and suppression mediating molecules. As the total Treg population does not increase in operational tolerance, it is the activated Treg which may be the most informative to monitor. Here we review the methods used to monitor peripheral Treg, the effect of immunosuppressive regimens on Treg, and correlations with clinical outcomes such as graft survival and rejection. Experimental therapies involving ex vivo Treg expansion and administration in renal transplantation are not reviewed.
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Affiliation(s)
- Jason Cheung
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
| | | | - Michael Suranyi
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | | | - Jason Diep
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Stephen T. Spicer
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Nirupama D. Verma
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Suzanne J. Hodgkinson
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
| | - Bruce M. Hall
- Renal Unit, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales (UNSW), Sydney, NSW, Australia
- Immune Tolerance Laboratory, Ingham Institute for Applied Medical Research, University of New South Wales (UNSW), Sydney, NSW, Australia
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Eslami MM, Rezaei R, Abdollahi S, Davari A, Ahmadvand M. FAS-670A＞G gene polymorphism and the risk of allograft rejection after organ transplantation: a systematic review and meta-analysis. Blood Res 2021; 56:17-25. [PMID: 33707352 PMCID: PMC7987476 DOI: 10.5045/br.2021.2020201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/12/2020] [Accepted: 02/23/2021] [Indexed: 11/17/2022] Open
Abstract
The association between the risk of allograft rejection after organ transplantation and FAS gene polymorphism has been evaluated previously. However, inconsistent results have been reported. Hence, we conducted the most up-to-date meta-analysis to evaluate this association. All eligible studies reporting the association between FAS-670A＞G polymorphism and the risk of allograft rejection published up to December 2019 were extracted using a comprehensive systematic database search in the Web of Science, Scopus, and PubMed. The pooled odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated to determine the association strength. This meta-analysis included six case-control studies with 277 patients who experienced allograft rejection and 1,001 patients who did not experience allograft rejection (controls) after organ transplantation. The overall results showed no significant association between FAS-670A＞G polymorphism and the risk of allograft rejection in five genetic models (dominant model: OR=0.81, 95% CI=0.58‒1.12; recessive model: OR=0.10, 95% CI=0.80‒1.53; allelic model: OR=0.96, 95% CI=0.79‒1.18; GG vs. AA: OR=0.92, 95% CI=0.62‒1.36; and AG vs. AA: OR=0.75, 95% CI=0.52‒1.08). Moreover, subgroup analysis according to ethnicity and age did not reveal statistically significant results. Our findings suggest that FAS-670A＞G polymorphism is not associated with the risk of allograft rejection after organ transplantation.
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Affiliation(s)
- Mohammad Masoud Eslami
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ramazan Rezaei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Sari, Iran
| | - Sara Abdollahi
- Mazandaran Faculty of Paramedical Sciences, Mazandaran University of Medical Sciences, Sari, Iran
| | - Afshin Davari
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran, Iran
| | - Mohammad Ahmadvand
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Adaptive features of innate immune cells and their relevance to graft rejection. Curr Opin Organ Transplant 2020; 24:664-669. [PMID: 31577598 DOI: 10.1097/mot.0000000000000707] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW Allograft rejection involves both innate and adaptive immune cells, and the adaptive immune cells have dominated transplant studies for decades. Recent studies have identified surprising new features for the innate immune cells, including memory recall responses, which may have significant implications in further improvement of transplant outcomes. RECENT FINDINGS Transplant survival is excellent in the short-term, but the long-term graft outcomes are not so, and most grafts are continuously lost to chronic rejection in the clinic. In both animal models and clinical settings, graft loss to chronic rejection is often dominated by innate immune cells, especially macrophages and natural killer (NK) cells in the grafts. Recent studies suggest that innate immune cells can acquire features of adaptive cells in that they either directly sense allogeneic nonself or become 'trained' in the allogeneic milieu, where they show features of memory recall responses. In certain models, targeting the adaptive features of such innate immune cells can promote long-term allograft survival. These findings may open new therapeutic opportunities in promoting transplant survival in the clinic. SUMMARY The discovery of donor specificity and memory recall responses of certain innate immune cells, which are prominently featured in chronic allograft rejection, may open novel therapeutic opportunities in transplantation, as well as in treatment of cancers and autoimmune diseases.
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Keshavarz Shahbaz S, Foroughi F, Soltaninezhad E, Jamialahmadi T, Penson PE, Sahebkar A. Application of PLGA nano/microparticle delivery systems for immunomodulation and prevention of allotransplant rejection. Expert Opin Drug Deliv 2020; 17:767-780. [PMID: 32223341 DOI: 10.1080/17425247.2020.1748006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Allograft transplantation is an effective end-point therapy to replace the function of an impaired organ. The main problem associated with allotransplantation is the induction of immune responses that results in acute and chronic graft rejection. To modulate the response of the immune system, transplant recipients generally take high dose immunosuppressant drugs for life. These drugs are associated with serious side effects such as infection with opportunistic pathogens and the development of neoplasia. AREAS COVERED We reviewed the obstacles to successful transplantation and PLGA-based strategies to reduce immune-mediated allograft rejection. EXPERT OPINION Biomaterial-based approaches using micro- and nanoparticles such as poly (lactic-co-glycolic acid) (PLGA) can be used to achieve controlled release of drugs. This approach decreases the required effective dose of drugs and enables local delivery of these agents to specific tissues and cells, whilst decreasing systemic effects.
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Affiliation(s)
- Sanaz Keshavarz Shahbaz
- Department of Immunology, School of Medicine, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Farshad Foroughi
- Cellular and Molecular Research Center, Qazvin University of Medical Sciences , Qazvin, Iran
| | - Ehsan Soltaninezhad
- Department of Immunology, Faculty of Medical Science, Tarbiat Modares University , Tehran, Iran
| | - Tannaz Jamialahmadi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences , Mashhad, Iran.,Department of Nutrition, Mashhad University of Medical Sciences , Mashhad, Iran
| | - Peter E Penson
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , Liverpool, UK
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA , Tehran, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences , Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences , Mashhad, Iran
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7
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Hamers AAJ, Joshi SK, Pillai AB. Innate Immune Determinants of Graft-Versus-Host Disease and Bidirectional Immune Tolerance in Allogeneic Transplantation. ACTA ACUST UNITED AC 2019; 3. [PMID: 33511333 PMCID: PMC7839993 DOI: 10.21926/obm.transplant.1901044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The success of tissue transplantation from a healthy donor to a diseased individual (allo-transplantation) is regulated by the immune systems of both donor and recipient. Developing a state of specific non-reactivity between donor and recipient, while maintaining the salutary effects of immune function in the recipient, is called “immune (transplantation) tolerance”. In the classic early post-transplant period, minimizing bidirectional donor ←→ recipient reactivity requires the administration of immunosuppressive drugs, which have deleterious side effects (severe immunodeficiency, opportunistic infections, and neoplasia, in addition to drug-specific reactions and organ toxicities). Inducing immune tolerance directly through donor and recipient immune cells, particularly via subsets of immune regulatory cells, has helped to significantly reduce side effects associated with multiple immunosuppressive drugs after allo-transplantation. The innate and adaptive arms of the immune system are both implicated in inducing immune tolerance. In the present article, we will review innate immune subset manipulations and their potential applications in hematopoietic stem cell transplantation (HSCT) to cure malignant and non-malignant hematological disorders by inducing long-lasting donor ←→ recipient (bidirectional) immune tolerance and reduced graft-versus-host disease (GVHD). These innate immunotherapeutic strategies to promote long-term immune allo-transplant tolerance include myeloid-derived suppressor cells (MDSCs), regulatory macrophages, tolerogenic dendritic cells (tDCs), Natural Killer (NK) cells, invariant Natural Killer T (iNKT) cells, gamma delta T (γδ-T) cells and mesenchymal stromal cells (MSCs).
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Affiliation(s)
- Anouk A J Hamers
- Department of Pediatrics, Division of Hematology / Oncology and Bone Marrow Transplantation, University of Miami Miller School of Medicine, Miami, FL, USA.,Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sunil K Joshi
- Department of Pediatrics, Division of Hematology / Oncology and Bone Marrow Transplantation, University of Miami Miller School of Medicine, Miami, FL, USA.,Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Asha B Pillai
- Department of Pediatrics, Division of Hematology / Oncology and Bone Marrow Transplantation, University of Miami Miller School of Medicine, Miami, FL, USA.,Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Holtz Children's Hospital, University of Miami Miller School of Medicine, Miami, FL, USA
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8
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Wang AYL, Loh CYY, Chen SJ, Kao HK, Lin CH, Chuang SH, Lee CM, Sytwu HK, Wei FC. Blimp-1 prolongs allograft survival without regimen via influencing T cell development in favor of regulatory T cells while suppressing Th1. Mol Immunol 2018; 99:53-65. [PMID: 29698799 DOI: 10.1016/j.molimm.2018.04.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 03/16/2018] [Accepted: 04/05/2018] [Indexed: 02/03/2023]
Abstract
BACKGROUND B lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown. METHODS This study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp-1. RESULTS Without any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation. DISCUSSION As such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'.
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Affiliation(s)
- Aline Yen Ling Wang
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
| | - Charles Yuen Yung Loh
- Division of Surgery and Interventional Science, University College London, London, United Kingdom; St Andrew's Center for Burns and Plastic Surgery, Chelmsford, United Kingdom
| | - Shyi-Jou Chen
- Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Department of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Huang-Kai Kao
- Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Sheng-Hao Chuang
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chin-Ming Lee
- Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Huey-Kang Sytwu
- Department of Microbiology and Immunology, Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Fu-Chan Wei
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Plastic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
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9
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Liu XG, Liu Y, Chen F. Soluble fibrinogen like protein 2 (sFGL2), the novel effector molecule for immunoregulation. Oncotarget 2018; 8:3711-3723. [PMID: 27732962 PMCID: PMC5356913 DOI: 10.18632/oncotarget.12533] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 09/29/2016] [Indexed: 02/07/2023] Open
Abstract
Soluble fibrinogen-like protein 2 (sFGL2) is the soluble form of fibrinogen-like protein 2 belonging to the fibrinogen-related protein superfamily. It is now well characterized that sFGL2 is mainly secreted by regulatory T cell (Treg) populations, and exerts potently immunosuppressive activities. By repressing not only the differentiation and proliferation of T cells but also the maturation of dendritic cells (DCs), sFGL2 acts largely as an immunosuppressant. Moreover, sFGL2 also induces apoptosis of B cells, tubular epithelial cells (TECs), sinusoidal endothelial cells (SECs), and hepatocytes. This mini-review focuses primarily on the recent literature with respect to the signaling mechanism of sFGL2 in immunomodulation, and discusses the clinical implications of sFGL2 in transplantation, hepatitis, autoimmunity, and tumors.
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Affiliation(s)
- Xin-Guang Liu
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, P. R. China
| | - Yu Liu
- School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology, Jinan, P. R. China
| | - Feng Chen
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, P. R. China.,Capital Medical University Cancer Center, Beijing Shijitan Hospital, Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing, China
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10
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Kotsougiani D, Hundepool CA, Bulstra LF, Friedrich PF, Shin AY, Bishop AT. Bone vascularized composite allotransplantation model in swine tibial defect: Evaluation of surgical angiogenesis and transplant viability. Microsurgery 2018; 39:160-166. [PMID: 29504151 DOI: 10.1002/micr.30310] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/02/2018] [Accepted: 02/08/2018] [Indexed: 11/10/2022]
Abstract
INTRODUCTION In prior small animal studies, we maintained vascularized bone allotransplant viability without long-term immunotherapy. Instead, an autogenous neoangiogenic circulation is created from implanted vessels, sufficient to maintain bone viability with only 2 weeks immunosupression. Blood flow is maintained despite rejection of the allogeneic vascular pedicle thereafter. We have previously described a large animal (swine) pre-clinical model, reconstructing tibial defects with vascularized tibial allotransplants. In this manuscript, autologous angiogenesis is evaluated in this model and correlated with bone viability. MATERIALS AND METHODS Allogeneic tibial segments were transplanted across a major swine leukocyte antigen mismatch. Microvascular repair of the bone VCA pedicle was combined with intraosseous implantation of an autogenous arteriovenous (AV) bundle. The bundle was ligated in group 1 (n = 4), and allowed to perfuse in group 2 (n = 4). Three-drug immunotherapy was given for 2 weeks. At 16 weeks micro-CT angiography quantified neoangiogenic vessel volume. Bone viability, rejection grade, and bone healing were analyzed. RESULTS A substantial neoangiogenic circulation developed from the implanted AV-bundle in group 2, with vessel density superior to ligated AV-bundle controls (0.11 ± 0.05 vs. 0.01 ± 0.01, P = .029). Bone allotransplant viability was also significantly enhanced by neoangiogenesis (78.7 ± 4.4% vs. 27.7 ± 5.8%, P = .028) with higher bone healing scores (21.4 ± 2.9 vs. 12.5 ± 3.7, P = .029). Ligated control tibias demonstrated disorganized bone morphology and higher local inflammation (P = .143). CONCLUSION Implantation of autogenous AV bundles into vascularized bone allotransplants resulted in the rapid formation of a neoangiogenic autogenous blood supply in a swine tibia model that maintained bone viability, improved bone healing, and minimized rejection.
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Affiliation(s)
- Dimitra Kotsougiani
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.,Department of Hand, Plastic and Reconstructive Surgery, Burn Center, BG Trauma Center Ludwigshafen, Department of Plastic Surgery, University of Heidelberg, Heidelberg, Germany
| | - Caroline A Hundepool
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Liselotte F Bulstra
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Patricia F Friedrich
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Alexander Y Shin
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Allen T Bishop
- Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
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11
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Kaundal U, Bagai U, Rakha A. Immunomodulatory plasticity of mesenchymal stem cells: a potential key to successful solid organ transplantation. J Transl Med 2018; 16:31. [PMID: 29448956 PMCID: PMC5815241 DOI: 10.1186/s12967-018-1403-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/07/2018] [Indexed: 02/06/2023] Open
Abstract
Organ transplantation remains to be a treatment of choice for patients suffering from irreversible organ failure. Immunosuppressive (IS) drugs employed to maintain the allograft have shown excellent short-term graft survival, but, their long-term use could contribute to immunological and non-immunological risk factors, resulting in graft dysfunctionalities. Upcoming IS regimes have highlighted the use of cell-based therapies, which can eliminate the risk of drug-borne toxicities while maintaining efficacy of the treatment. Mesenchymal stem cells (MSCs) have been considered as an invaluable cell type, owing to their unique immunomodulatory properties, which makes them desirable for application in transplant settings, where hyper-activation of the immune system is evident. The immunoregulatory potential of MSCs holds true for preclinical studies while achieving it in clinical studies continues to be a challenge. Understanding the biological factors responsible for subdued responses of MSCs in vivo would allow uninhibited use of this therapy for countless conditions. In this review, we summarize the variations in the preclinical and clinical studies utilizing MSCs, discuss the factors which might be responsible for variability in outcome and propose the advancements likely to occur in future for using this as a "boutique/personalised therapy" for patient care.
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Affiliation(s)
- Urvashi Kaundal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
- Department of Zoology, Panjab University, Sector 14, Chandigarh, India
| | - Upma Bagai
- Department of Zoology, Panjab University, Sector 14, Chandigarh, India
| | - Aruna Rakha
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
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12
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Bontha SV, Fernandez-Piñeros A, Maluf DG, Mas VR. Messengers of tolerance. Hum Immunol 2018; 79:362-372. [PMID: 29402484 DOI: 10.1016/j.humimm.2018.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/16/2018] [Accepted: 01/19/2018] [Indexed: 12/21/2022]
Abstract
The use of immunosuppressant drugs after organ transplantation has brought great success in the field of organ transplantation with respect to short-term outcome. However, major challenges (i.e., limited improvement of long-term survival, immunosuppressant toxicity, infections and carcinoma) demand alternate treatment approaches that minimizes the use of immunosuppressants. Interestingly, few studies have identified groups of transplant patients who developed operational tolerance and thereby keep their allograft without complications in absence of immunosuppressants. These rare groups of patients are of particular interest as study subjects for understanding mechanisms of graft tolerance that could be leveraged in future for inducing tolerance and for understanding mechanisms involved in improving long-term allograft outcomes. Also, biomarkers from these studies could benefit the larger transplant population by their application in immunosuppressant tailoring and identification of tolerant patients among patients with stably functioning allografts. This review compiles several gene expression studies performed in samples from tolerant patients in different solid organ transplantations to identify key genes and associated molecular pathways relevant to tolerance. This review is aimed at putting forth all this important work done thus far and to identify research gaps that need to be filled, in order to achieve the greater purpose of these studies.
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Affiliation(s)
- Sai Vineela Bontha
- Translational Genomics and Transplant Laboratory, Department of Surgery, University of Virginia, Charlottesville 22903, United States
| | - Angela Fernandez-Piñeros
- Translational Genomics and Transplant Laboratory, Department of Surgery, University of Virginia, Charlottesville 22903, United States
| | - Daniel G Maluf
- Translational Genomics and Transplant Laboratory, Department of Surgery, University of Virginia, Charlottesville 22903, United States; Transplant Surgery, Department of Surgery, University of Virginia, Charlottesville 22903, United States
| | - Valeria R Mas
- Translational Genomics and Transplant Laboratory, Department of Surgery, University of Virginia, Charlottesville 22903, United States.
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13
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Vanikar AV, Trivedi HL, Thakkar UG. Six years' experience of tolerance induction in renal transplantation using stem cell therapy. Clin Immunol 2018; 187:10-14. [DOI: 10.1016/j.clim.2017.07.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/26/2017] [Indexed: 01/14/2023]
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14
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Contreras-Kallens P, Terraza C, Oyarce K, Gajardo T, Campos-Mora M, Barroilhet MT, Álvarez C, Fuentes R, Figueroa F, Khoury M, Pino-Lagos K. Mesenchymal stem cells and their immunosuppressive role in transplantation tolerance. Ann N Y Acad Sci 2017; 1417:35-56. [PMID: 28700815 DOI: 10.1111/nyas.13364] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/13/2017] [Accepted: 03/29/2017] [Indexed: 12/23/2022]
Abstract
Since they were first described, mesenchymal stem cells (MSCs) have been shown to have important effector mechanisms and the potential for use in cell therapy. A great deal of research has been focused on unveiling how MSCs contribute to anti-inflammatory responses, including describing several cell populations involved and identifying soluble and other effector molecules. In this review, we discuss some of the contemporary evidence for use of MSCs in the field of immune tolerance, with a special emphasis on transplantation. Although considerable effort has been devoted to understanding the biological function of MSCs, additional resources are required to clarify the mechanisms of their induction of immune tolerance, which will undoubtedly lead to improved clinical outcomes for MSC-based therapies.
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Affiliation(s)
- Pamina Contreras-Kallens
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Claudia Terraza
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Karina Oyarce
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Tania Gajardo
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Mauricio Campos-Mora
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - María Teresa Barroilhet
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Carla Álvarez
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Ricardo Fuentes
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Fernando Figueroa
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Maroun Khoury
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Cells for Cells, Santiago, Chile.,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Karina Pino-Lagos
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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15
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Szadvari I, Krizanova O, Babula P. Athymic nude mice as an experimental model for cancer treatment. Physiol Res 2017; 65:S441-S453. [PMID: 28006926 DOI: 10.33549/physiolres.933526] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Athymic nude mice, a murine strain bearing spontaneous deletion in the Foxn1 gene that causes deteriorated or absent thymus (which results in inhibited immune system with reduction of number of T cells), represent a widely used model in cancer research having long lasting history as a tool for preclinical testing of drugs. The review describes three models of athymic mice that utilize cancer cell lines to induce tumors. In addition, various methods that can be applied in order to evaluate activity of anticancer agents in these models are shown and discussed. Although each model has certain disadvantages, they are still considered as inevitable instruments in many fields of cancer research, particularly in finding new drugs that would more effectively combat the cancer disease or enhance the use of current chemotherapy. Finally, the review summarizes strengths and weaknesses as well as future perspectives of the athymic nude mice model in cancer research.
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Affiliation(s)
- I Szadvari
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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16
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Sommer W, Buechler G, Jansson K, Avsar M, Knöfel AK, Salman J, Hoeffler K, Siemeni T, Gottlieb J, Karstens JH, Jonigk D, Reising A, Haverich A, Strüber M, Warnecke G. Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine. Transpl Int 2017; 30:420-431. [DOI: 10.1111/tri.12916] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 10/07/2016] [Accepted: 01/09/2017] [Indexed: 12/25/2022]
Affiliation(s)
- Wiebke Sommer
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
| | - Gwen Buechler
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
| | - Katharina Jansson
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
| | - Murat Avsar
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
| | - Ann-Kathrin Knöfel
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
| | - Jawad Salman
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
| | - Klaus Hoeffler
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
| | - Thierry Siemeni
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
| | - Jens Gottlieb
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
- Department of Respiratory Medicine; Hannover Medical School; Hannover Germany
| | - Johann H. Karstens
- Department of Nuclear Medicine and Radiation Oncology; Hannover Medical School; Hannover Germany
| | - Danny Jonigk
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
- Institute for Pathology; Hannover Medical School; Hannover Germany
| | - Ansgar Reising
- Department of Nephrology; Hannover Medical School; Hannover Germany
| | - Axel Haverich
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
| | - Martin Strüber
- Richard DeVos Heart & Lung Transplant Program; Frederik Meijer Heart & Vascular Institute; Grand Rapids MI USA
| | - Gregor Warnecke
- Department of Cardiac-, Thoracic-, Transplantation- and Vascular Surgery; Hannover Medical School; Hannover Germany
- German Centre for Lung Research; Hannover Medical School; Hannover Germany
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17
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Rohner NA, Thomas SN. Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size. ACS Biomater Sci Eng 2017; 3:153-159. [PMID: 29888321 PMCID: PMC5990040 DOI: 10.1021/acsbiomaterials.6b00438] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Therapeutic immunomodulation in the skin, its draining lymph nodes, or both tissues simultaneously using an intradermal administration scheme is desirable for a variety of therapeutic scenarios. To inform how drug carriers comprising engineered biomaterials can be leveraged to improve treatment efficacy by enhancing the selective accumulation or retention of payload within these target tissues, we analyzed the influence of particle versus macromolecule hydrodynamic size on profiles of retention in the site of dermal injection as well as the corresponding extent of accumulation in draining lymph nodes and systemic off-target tissues. Using a panel of fluorescently labeled tracers comprising inert polymers that are resistant to hydrolysis and proteolytic degradation that span a size range of widely used drug carrier systems, we find that macromolecule but not rigid particle retention within the skin is size-dependent, whereas the relative dermal enrichment compared to systemic tissues increases with size for both tracer types. Additionally, macromolecules 10 nm in hydrodynamic size and greater accumulate in draining lymph nodes more extensively and selectively than particles, suggesting that intra- versus extracellular availability of delivered payload within draining lymph nodes may be influenced by both the size and form of engineered drug carriers. Our results inform how biomaterial-based drug carriers can be designed to enhance the selective exposure of formulated drug in target tissues to improve the therapeutic efficacy as well as minimize off-target effects of locoregional immunotherapy.
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Affiliation(s)
- Nathan Andrew Rohner
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, Georgia 30332, United States
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, Georgia 30332, United States
| | - Susan Napier Thomas
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive, Atlanta, Georgia 30332, United States
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, Georgia 30332, United States
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, United States
- Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road Northeast, Atlanta, Georgia 30322, United States
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18
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Rossi L, Pierigè F, Antonelli A, Bigini N, Gabucci C, Peiretti E, Magnani M. Engineering erythrocytes for the modulation of drugs' and contrasting agents' pharmacokinetics and biodistribution. Adv Drug Deliv Rev 2016; 106:73-87. [PMID: 27189231 DOI: 10.1016/j.addr.2016.05.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 04/29/2016] [Accepted: 05/09/2016] [Indexed: 01/14/2023]
Abstract
Pharmacokinetics, biodistribution, and biological activity are key parameters that determine the success or failure of therapeutics. Many developments intended to improve their in vivo performance, aim at modulating concentration, biodistribution, and targeting to tissues, cells or subcellular compartments. Erythrocyte-based drug delivery systems are especially efficient in maintaining active drugs in circulation, in releasing them for several weeks or in targeting drugs to selected cells. Erythrocytes can also be easily processed to entrap the desired pharmaceutical ingredients before re-infusion into the same or matched donors. These carriers are totally biocompatible, have a large capacity and could accommodate traditional chemical entities (glucocorticoids, immunossuppresants, etc.), biologics (proteins) and/or contrasting agents (dyes, nanoparticles). Carrier erythrocytes have been evaluated in thousands of infusions in humans proving treatment safety and efficacy, hence gaining interest in the management of complex pathologies (particularly in chronic treatments and when side-effects become serious issues) and in new diagnostic approaches.
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19
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Edinur HA, Manaf SM, Che Mat NF. Genetic barriers in transplantation medicine. World J Transplant 2016; 6:532-541. [PMID: 27683631 PMCID: PMC5036122 DOI: 10.5500/wjt.v6.i3.532] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/26/2016] [Accepted: 07/13/2016] [Indexed: 02/05/2023] Open
Abstract
The successful of transplantation is determined by the shared human leukocyte antigens (HLAs) and ABO blood group antigens between donor and recipient. In recent years, killer cell receptor [i.e., killer cell immunoglobulin-like receptor (KIR)] and major histocompatibility complex (MHC) class I chain-related gene molecule (i.e., MICA) were also reported as important determinants of transplant compatibility. At present, several different genotyping techniques (e.g., sequence specific primer and sequence based typing) can be used to characterize blood group, HLA, MICA and KIR and loci. These molecular techniques have several advantages because they do not depend on the availability of anti-sera, cellular expression and have greater specificity and accuracy compared with the antibody-antigen based typing. Nonetheless, these molecular techniques have limited capability to capture increasing number of markers which have been demonstrated to determine donor and recipient compatibility. It is now possible to genotype multiple markers and to the extent of a complete sequencing of the human genome using next generation sequencer (NGS). This high throughput genotyping platform has been tested for HLA, and it is expected that NGS will be used to simultaneously genotype a large number of clinically relevant transplantation genes in near future. This is not far from reality due to the bioinformatics support given by the immunogenetics community and the rigorous improvement in NGS methodology. In addition, new developments in immune tolerance based therapy, donor recruitment strategies and bioengineering are expected to provide significant advances in the field of transplantation medicine.
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20
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Crescioli C. Chemokines and transplant outcome. Clin Biochem 2016; 49:355-62. [DOI: 10.1016/j.clinbiochem.2015.07.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 07/10/2015] [Accepted: 07/20/2015] [Indexed: 12/26/2022]
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21
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Effects of FVIII immunity on hepatocyte and hematopoietic stem cell-directed gene therapy of murine hemophilia A. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2016; 3:15056. [PMID: 26909355 PMCID: PMC4750467 DOI: 10.1038/mtm.2015.56] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 12/10/2015] [Accepted: 12/11/2015] [Indexed: 02/08/2023]
Abstract
Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.
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22
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Chessa F, Mathow D, Wang S, Hielscher T, Atzberger A, Porubsky S, Gretz N, Burgdorf S, Gröne HJ, Popovic ZV. The renal microenvironment modifies dendritic cell phenotype. Kidney Int 2016; 89:82-94. [DOI: 10.1038/ki.2015.292] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Revised: 07/20/2015] [Accepted: 08/06/2015] [Indexed: 12/20/2022]
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23
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A novel cyclic helix B peptide inhibits dendritic cell maturation during amelioration of acute kidney graft rejection through Jak-2/STAT3/SOCS1. Cell Death Dis 2015; 6:e1993. [PMID: 26610206 PMCID: PMC4670942 DOI: 10.1038/cddis.2015.338] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 09/22/2015] [Accepted: 10/09/2015] [Indexed: 12/23/2022]
Abstract
We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. Dendritic cells (DCs) play an activation role in acute rejection (AR). Thus, the present study was designed to investigate the effects of CHBP on DCs in a rat renal transplantation model. The left kidney was harvested from male Lewis rats and then transplanted into male Wistar rats with or without CHBP treatment. Five successive treatment doses of CHBP after transplantation significantly ameliorated AR with lower histological injury, apoptosis and CD4+ and CD8+ T-cell infiltration in renal allografts. CHBP reduced IFN-γ and IL-1β levels but increased IL-4 and IL-10 levels in the serum. The number of mature DCs was significantly decreased in renal allografts treated with CHBP. In addition, incubating DCs with CHBP in vitro led to reduction in TNF-α, IFN-γ, IL-1β and IL-12 levels and increase of IL-10 expression at the protein level in the supernatant. Mechanistically, CHBP inhibited TLR activation-induced DC maturation by increasing SOCS1 expression through Jak-2/STAT3 signaling. In conclusion, CHBP suppresses renal allograft AR by inhibiting the maturation of DCs via Jak-2/STAT3/SOCS1 signaling, suggesting that CHBP may be an potential therapeutic drug for treating renal AR.
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24
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Dittmar L, Mohr E, Kleist C, Ehser S, Demirdizen H, Sandra-Petrescu F, Hundemer M, Opelz G, Terness P. Immunosuppressive properties of mitomycin C-incubated human myeloid blood cells (MIC) in vitro. Hum Immunol 2015; 76:480-7. [PMID: 26074415 DOI: 10.1016/j.humimm.2015.06.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 04/01/2015] [Accepted: 06/02/2015] [Indexed: 10/23/2022]
Abstract
Previous animal studies showed that donor-derived blood cells treated with mitomycin C (MMC) prolong allograft survival when injected into recipients. This model was effective with whole blood, peripheral blood mononuclear cells (PBMC) (monocytes being the active cell subpopulation) or dendritic cells. In view of a potential clinical application, we study now the immunosuppressive properties of human myeloid cells in vitro. Mature dendritic cells (generated from naïve monocytes) or monocytes treated with mitomycin C do not or only weakly inhibit allogeneic T cells in vitro, whereas cells in an early differentiation state between monocytes and DC exert suppressive activity when treated with MMC. In contrast, DC generated from MMC-treated monocytes show the morphology and phenotype of early immature DC (iDC) and suppress T-cell responses. It is known that untreated monocytes injected into a recipient encounter a cytokine milieu which differentiates them to stimulatory DC. In our in vitro experiment MMC-treated monocytes cultured in a DC-maturing milieu transform themselves into suppressive early iDC. This reproduces a process which takes place when administering MMC-monocytes to a recipient. In conclusion, human MMC-DC or MMC-monocytes are not or only weakly suppressive in vitro. When MMC-monocytes are differentiated to DC the resulting cells become suppressive.
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Affiliation(s)
- Laura Dittmar
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Elisabeth Mohr
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Christian Kleist
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Sandra Ehser
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Haydar Demirdizen
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Flavius Sandra-Petrescu
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Michael Hundemer
- Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| | - Gerhard Opelz
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
| | - Peter Terness
- Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120 Heidelberg, Germany.
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Abstract
Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers CD4 and CD25 and forkhead box protein 3 (FoxP3). Tolerance could be transferred to syngeneic recipients with blood or spleen cells. Depletion of Tregs from tolerogenic cells abrogated their suppressive effect, arguing for mediation of immunosuppression by CD4⁺CD25⁺FoxP3⁺ Tregs. Donor-derived MICs also prolonged kidney allograft survival in pigs. MICs generated from donor monocytes were applied for the first time in humans in a patient suffering from therapy-resistant rejection of a haploidentical stem cell transplant. We describe, in the present paper, a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans.
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Padet L, Loubaki L, Bazin R. Use of IVIg to identify potential miRNA targets for allograft rejection and GvHD therapy. Clin Transplant 2015; 29:543-6. [PMID: 25832981 DOI: 10.1111/ctr.12549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2015] [Indexed: 11/26/2022]
Abstract
Allograft rejection (AR) and graft-versus-host disease (GvHD) are serious complications following transplantation. Micro-RNAs (miRNAs) have recently been identified as key players in the regulation of these disorders. Because intravenous immunoglobulin (IVIg) has shown therapeutic potential for the prophylaxis and post-transplant reduction of AR and GvHD, we hypothesized that the effect of IVIg could result from the modulation of specific miRNA expression. To identify such miRNA, we performed mixed lymphocyte reactions (MLRs) as an in vitro model of AR and GvHD, with or without IVIg. We herein show that IVIg strongly inhibits the MLRs. This inhibition is associated with a modulation in the expression of miRNAs implicated in the regulation of pro-inflammatory cytokine (IL-2, IL-6, IFN-γ) and costimulatory molecule (CD80) expression. We propose that these identified miRNAs could represent potential therapeutic targets for the prevention and therapy of AR and GvHD.
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Affiliation(s)
- Lauriane Padet
- Department of Research and Development, Héma-Québec, Québec, Canada.,Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Québec, Canada
| | - Lionel Loubaki
- Department of Research and Development, Héma-Québec, Québec, Canada
| | - Renée Bazin
- Department of Research and Development, Héma-Québec, Québec, Canada.,Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Québec, Canada
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28
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Salvadori M, Bertoni E. What's new in clinical solid organ transplantation by 2013. World J Transplant 2014; 4:243-266. [PMID: 25540734 PMCID: PMC4274595 DOI: 10.5500/wjt.v4.i4.243] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 07/11/2014] [Accepted: 07/27/2014] [Indexed: 02/05/2023] Open
Abstract
Innovative and exciting advances in the clinical science in solid organ transplantation continuously realize as the results of studies, clinical trials, international conferences, consensus conferences, new technologies and discoveries. This review will address to the full spectrum of news in transplantation, that verified by 2013. The key areas covered are the transplantation activity, with particular regards to the donors, the news for solid organs such as kidney, pancreas, liver, heart and lung, the news in immunosuppressive therapies, the news in the field of tolerance and some of the main complications following transplantation as infections and cancers. The period of time covered by the study starts from the international meetings held in 2012, whose results were published in 2013, up to the 2013 meetings, conferences and consensus published in the first months of 2014. In particular for every organ, the trends in numbers and survival have been reviewed as well as the most relevant problems such as organ preservation, ischemia reperfusion injuries, and rejections with particular regards to the antibody mediated rejection that involves all solid organs. The new drugs and strategies applied in organ transplantation have been divided into new way of using old drugs or strategies and drugs new not yet on the market, but on phase Ito III of clinical studies and trials.
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Sabatino R, Antonelli A, Battistelli S, Schwendener R, Magnani M, Rossi L. Macrophage depletion by free bisphosphonates and zoledronate-loaded red blood cells. PLoS One 2014; 9:e101260. [PMID: 24968029 PMCID: PMC4072741 DOI: 10.1371/journal.pone.0101260] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 06/04/2014] [Indexed: 02/08/2023] Open
Abstract
Bisphosphonates, besides being important drugs for the treatment of various bone diseases, could also be used to induce apoptosis in macrophage-like and cancer cells. However, their activity in vivo is limited by a short plasma half-life and rapid uptake within bone. Therefore, several delivery systems have been proposed to modify their pharmacokinetic profile and biodistribution. Among these, red blood cells (RBCs) represent one of the most promising biological carriers. The aim of this study was to select the best performing compound among Clodronate, Pamidronate, Ibandronate and Zoledronate in killing macrophages and to investigate RBCs as innovative carrier system to selectively target bisphosphonates to macrophages. To this end, the encapsulation of the selected bisphosphonates in autologous RBCs as well as the effect on macrophages, both in vitro and in vivo were studied. This work shows that, among the tested bisphosphonates, Zoledronate has proven to be the most active molecule. Human and murine RBCs have been successfully loaded with Zoledronate by a procedure of hypotonic dialysis and isotonic resealing, obtaining a dose-dependent drug entrapment with a maximal loading of 7.96±2.03, 6.95±3.9 and 7.0±1.89 µmoles of Zoledronate/ml of packed RBCs for human, Swiss and Balb/C murine RBCs, respectively. Engineered RBCs were able to detach human and murine macrophages in vitro, leading to a detachment of 66±8%, 67±8% and 60.5±3.5% for human, Swiss and Balb/C RBCs, respectively. The in vivo efficacy of loaded RBCs was tested in Balb/C mice administering 59 µg/mouse of RBC-encapsulated Zoledronate. By a single administration, depletion of 29.0±16.38% hepatic macrophages and of 67.84±5.48% spleen macrophages was obtained, confirming the ability of encapsulated Zoledronate to deplete macrophages in vivo. In conclusion, RBCs loaded with Zoledronate should be considered a suitable system for targeted delivery to macrophages, both in vitro and in vivo.
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Affiliation(s)
- Raffaella Sabatino
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino (PU), Italy
| | - Antonella Antonelli
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino (PU), Italy
| | - Serafina Battistelli
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino (PU), Italy
| | - Reto Schwendener
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Mauro Magnani
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino (PU), Italy
- EryDel SpA, Urbino (PU), Italy
| | - Luigia Rossi
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino (PU), Italy
- EryDel SpA, Urbino (PU), Italy
- * E-mail:
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