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Zhao S, Hu Y, Yang B, Zhang L, Xu M, Jiang K, Liu Z, Wu M, Huang Y, Li P, Liang SJ, Sun X, Hide G, Lun ZR, Wu Z, Shen J. The transplant rejection response involves neutrophil and macrophage adhesion-mediated trogocytosis and is regulated by NFATc3. Cell Death Dis 2024; 15:75. [PMID: 38242872 PMCID: PMC10798984 DOI: 10.1038/s41419-024-06457-4] [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: 10/02/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/21/2024]
Abstract
The anti-foreign tissue (transplant rejection) response, mediated by the immune system, has been the biggest obstacle to successful organ transplantation. There are still many enigmas regarding this process and some aspects of the underlying mechanisms driving the immune response against foreign tissues remain poorly understood. Here, we found that a large number of neutrophils and macrophages were attached to the graft during skin transplantation. Furthermore, both types of cells could autonomously adhere to and damage neonatal rat cardiomyocyte mass (NRCM) in vitro. We have demonstrated that Complement C3 and the receptor CR3 participated in neutrophils/macrophages-mediated adhesion and damage this foreign tissue (NRCM or skin grafts). We have provided direct evidence that the damage to these tissues occurs by a process referred to as trogocytosis, a damage mode that has never previously been reported to directly destroy grafts. We further demonstrated that this process can be regulated by NFAT, in particular, NFATc3. This study not only enriches an understanding of host-donor interaction in transplant rejection, but also provides new avenues for exploring the development of novel immunosuppressive drugs which prevent rejection during transplant therapy.
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Affiliation(s)
- Siyu Zhao
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Yunyi Hu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Bicheng Yang
- The Andrology Department, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Lichao Zhang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Meiyining Xu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Kefeng Jiang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Zhun Liu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
| | - Mingrou Wu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Yun Huang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Peipei Li
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Si-Jia Liang
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Sun Yat-sen University, 74 Zhongshan 2 Rd, Guangzhou, 510080, China
| | - Xi Sun
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Geoff Hide
- Biomedical Research and Innovation Centre, School of Science, Engineering and Environment, University of Salford, Salford, M5 4WT, UK
| | - Zhao-Rong Lun
- Biomedical Research and Innovation Centre, School of Science, Engineering and Environment, University of Salford, Salford, M5 4WT, UK
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Zhongdao Wu
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China
| | - Jia Shen
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.
- Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, Guangdong, China.
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, Guangdong, China.
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Zhao S, Zhang L, Xiang S, Hu Y, Wu Z, Shen J. Gnawing Between Cells and Cells in the Immune System: Friend or Foe? A Review of Trogocytosis. Front Immunol 2022; 13:791006. [PMID: 35185886 PMCID: PMC8850298 DOI: 10.3389/fimmu.2022.791006] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 01/14/2022] [Indexed: 12/27/2022] Open
Abstract
Trogocytosis occurs when one cell contacts and quickly nibbles another cell and is characterized by contact between living cells and rapid transfer of membrane fragments with functional integrity. Many immune cells are involved in this process, such as T cells, B cells, NK cells, APCs. The transferred membrane molecules including MHC molecules, costimulatory molecules, receptors, antigens, etc. An increasing number of studies have shown that trogocytosis plays an important role in the immune system and the occurrence of relevant diseases. Thus, whether trogocytosis is a friend or foe of the immune system is puzzling, and the precise mechanism underlying it has not yet been fully elucidated. Here, we provide an integrated view of the acquired findings on the connections between trogocytosis and the immune system.
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Affiliation(s)
- Siyu Zhao
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Lichao Zhang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Suoyu Xiang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Yunyi Hu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Zhongdao Wu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
| | - Jia Shen
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China
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3
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Trogocytosis between Non-Immune Cells for Cell Clearance, and among Immune-Related Cells for Modulating Immune Responses and Autoimmunity. Int J Mol Sci 2021; 22:ijms22052236. [PMID: 33668117 PMCID: PMC7956485 DOI: 10.3390/ijms22052236] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/21/2021] [Accepted: 02/21/2021] [Indexed: 12/21/2022] Open
Abstract
The term trogocytosis refers to a rapid bidirectional and active transfer of surface membrane fragment and associated proteins between cells. The trogocytosis requires cell-cell contact, and exhibits fast kinetics and the limited lifetime of the transferred molecules on the surface of the acceptor cells. The biological actions of trogocytosis include information exchange, cell clearance of unwanted tissues in embryonic development, immunoregulation, cancer surveillance/evasion, allogeneic cell survival and infectious pathogen killing or intercellular transmission. In the present review, we will extensively review all these aspects. In addition to its biological significance, aberrant trogocytosis in the immune system leading to autoimmunity and immune-mediated inflammatory diseases will also be discussed. Finally, the prospective investigations for further understanding the molecular basis of trogocytosis and its clinical applications will also be proposed.
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Abstract
Trogocytosis is part of an emerging, exciting theme of cell-cell interactions both within and between species, and it is relevant to host-pathogen interactions in many different contexts. Trogocytosis is a process in which one cell physically extracts and ingests "bites" of cellular material from another cell. It was first described in eukaryotic microbes, where it was uncovered as a mechanism by which amoebae kill cells. Trogocytosis is potentially a fundamental form of eukaryotic cell-cell interaction, since it also occurs in multicellular organisms, where it has functions in the immune system, in the central nervous system, and during development. There are numerous scenarios in which trogocytosis occurs and an ever-evolving list of functions associated with this process. Many aspects of trogocytosis are relevant to microbial pathogenesis. It was recently discovered that immune cells perform trogocytosis to kill Trichomonas vaginalis parasites. Additionally, through trogocytosis, Entamoeba histolytica acquires and displays human cell membrane proteins, enabling immune evasion. Intracellular bacteria seem to exploit host cell trogocytosis, since they can use it to spread from cell to cell. Thus, a picture is emerging in which trogocytosis plays critical roles in normal physiology, infection, and disease.
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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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6
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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7
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Screening and analysis of breast cancer genes regulated by the human mammary microenvironment in a humanized mouse model. Oncol Lett 2016; 12:5261-5268. [PMID: 28101242 DOI: 10.3892/ol.2016.5310] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 03/09/2016] [Indexed: 01/02/2023] Open
Abstract
Tumor microenvironments play critical regulatory roles in tumor growth. Although mouse cancer models have contributed to the understanding of human tumor biology, the effectiveness of mouse cancer models is limited by the inability of the models to accurately present humanized tumor microenvironments. Previously, a humanized breast cancer model in severe combined immunodeficiency mice was established, in which human breast cancer tissue was implanted subcutaneously, followed by injection of human breast cancer cells. It was demonstrated that breast cancer cells showed improved growth in the human mammary microenvironment compared with a conventional subcutaneous mouse model. In the present study, the novel mouse model and microarray technology was used to analyze changes in the expression of genes in breast cancer cells that are regulated by the human mammary microenvironment. Humanized breast and conventional subcutaneous mouse models were established, and orthotopic tumor cells were obtained from orthotopic tumor masses by primary culture. An expression microarray using Illumina HumanHT-12 v4 Expression BeadChip and database analyses were performed to investigate changes in gene expression between tumors from each microenvironment. A total of 94 genes were differentially expressed between the primary cells cultured from the humanized and conventional mouse models. Significant upregulation of genes that promote cell proliferation and metastasis or inhibit apoptosis, such as SH3-domain binding protein 5 (BTK-associated), sodium/chloride cotransporter 3 and periostin, osteoblast specific factor, and genes that promote angiogenesis, such as KIAA1618, was also noted. Other genes that restrain cell proliferation and accelerate cell apoptosis, including tripartite motif containing TRIM36 and NES1, were downregulated. The present results revealed differences in various aspects of tumor growth and metabolism between the two model groups and indicated the functional changes specific to the human mammary microenvironment.
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Boudreau JE, Liu XR, Zhao Z, Zhang A, Shultz LD, Greiner DL, Dupont B, Hsu KC. Cell-Extrinsic MHC Class I Molecule Engagement Augments Human NK Cell Education Programmed by Cell-Intrinsic MHC Class I. Immunity 2016; 45:280-91. [PMID: 27496730 DOI: 10.1016/j.immuni.2016.07.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 04/23/2016] [Accepted: 05/22/2016] [Indexed: 11/19/2022]
Abstract
The effector potential of NK cells is counterbalanced by their sensitivity to inhibition by "self" MHC class I molecules in a process called "education." In humans, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and human MHC (HLA) mediate NK cell education. In HLA-B(∗)27:05(+) transgenic mice and in patients undergoing HLA-mismatched hematopoietic cell transplantation (HCT), NK cells derived from human CD34(+) stem cells were educated by HLA from both donor hematopoietic cells and host stromal cells. Furthermore, mature human KIR3DL1(+) NK cells gained reactivity after adoptive transfer to HLA-B(∗)27:05(+) mice or bone marrow chimeric mice where HLA-B(∗)27:05 was restricted to either the hematopoietic or stromal compartment. Silencing of HLA in primary NK cells diminished NK cell reactivity, while acquisition of HLA from neighboring cells increased NK cell reactivity. Altogether, these findings reveal roles for cell-extrinsic HLA in driving NK cell reactivity upward, and cell-intrinsic HLA in maintaining NK cell education.
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Affiliation(s)
- Jeanette E Boudreau
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Xiao-Rong Liu
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Zeguo Zhao
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Aaron Zhang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | | | - Dale L Greiner
- Program in Molecular Medicine Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Bo Dupont
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Katharine C Hsu
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
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Steele S, Radlinski L, Taft-Benz S, Brunton J, Kawula TH. Trogocytosis-associated cell to cell spread of intracellular bacterial pathogens. eLife 2016; 5. [PMID: 26802627 PMCID: PMC4786427 DOI: 10.7554/elife.10625] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 01/22/2016] [Indexed: 11/13/2022] Open
Abstract
Macrophages are myeloid-derived phagocytic cells and one of the first immune cell types to respond to microbial infections. However, a number of bacterial pathogens are resistant to the antimicrobial activities of macrophages and can grow within these cells. Macrophages have other immune surveillance roles including the acquisition of cytosolic components from multiple types of cells. We hypothesized that intracellular pathogens that can replicate within macrophages could also exploit cytosolic transfer to facilitate bacterial spread. We found that viable Francisella tularensis, as well as Salmonella enterica bacteria transferred from infected cells to uninfected macrophages along with other cytosolic material through a transient, contact dependent mechanism. Bacterial transfer occurred when the host cells exchanged plasma membrane proteins and cytosol via a trogocytosis related process leaving both donor and recipient cells intact and viable. Trogocytosis was strongly associated with infection in mice, suggesting that direct bacterial transfer occurs by this process in vivo.
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Affiliation(s)
- Shaun Steele
- University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Lauren Radlinski
- University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Sharon Taft-Benz
- University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Jason Brunton
- University of North Carolina at Chapel Hill, Chapel Hill, United States
| | - Thomas H Kawula
- University of North Carolina at Chapel Hill, Chapel Hill, United States
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Hivelin M, Klimczak A, Cwykiel J, Sonmez E, Nasir S, Gatherwright J, Siemionow M. Immunomodulatory Effects of Different Cellular Therapies of Bone Marrow Origin on Chimerism Induction and Maintenance Across MHC Barriers in a Face Allotransplantation Model. Arch Immunol Ther Exp (Warsz) 2015; 64:299-310. [PMID: 26708158 DOI: 10.1007/s00005-015-0380-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 10/05/2015] [Indexed: 01/31/2023]
Abstract
Many more patients would benefit from vascularized composite allotransplantation if less toxic and safer immunosuppressive protocols will become available. Tolerance induction protocols with donor cells co-transplantation are one of the promising pathways to reduce maintenance immunosupressive regimens. We investigated the role of donor bone marrow cells (BMC), mesenchymal stromal cells (MSC) and in vivo created chimeric cells (CC) used as supportive therapies in a fully MHC-mismatched rat face transplantation model. Twenty-four fully MHC-mismatched hemiface transplantations were performed between ACI (RT1(a)) donors and Lewis (RT1(l)) recipients under combined seven-day immunosuppressive regimen of anti-αβ-T-cell receptor (TCR) monoclonal antibody and cyclosporin A. We studied four experimental groups-group 1: no cellular therapy; group 2: supportive therapy with BMC; group 3: supportive therapy with MSC; group 4: supportive therapy with CC generated in a primary chimera. We evaluated clinical and histological rejection grades, transplanted cells migration, donor-specific chimerism in the peripheral blood and bone marrow compartments, and CD4(+)/CD25(+) T-cell levels. Face allograft rejection was observed at 26.8 ± 0.6 days post-transplant (PT) in the absence of cellular therapy, at 34.5 ± 1.1 days for group 2, 29.3 ± 0.8 days for group 3, and 30.3 ± 1.38 PT for group 4. The longest survival was observed in allografts supported by co-transplantation of BMC. All support in cellular therapies delayed face allograft rejection by chimerism induction and/or immunomodulatory properties of co-transplanted cells. Survival time was comparable between groups, however, further studies, with different cell dosages, delivery routes and delivery times are required.
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Affiliation(s)
- Mikael Hivelin
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Aleksandra Klimczak
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Joanna Cwykiel
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA.,Department of Orthopedics, University of Illinois at Chicago, Chicago, IL, USA
| | - Erhan Sonmez
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Serdar Nasir
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA
| | | | - Maria Siemionow
- Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, USA. .,Department of Orthopedics, University of Illinois at Chicago, Chicago, IL, USA.
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11
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CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection. Proc Natl Acad Sci U S A 2015; 112:12788-93. [PMID: 26420874 DOI: 10.1073/pnas.1513533112] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen "indirectly," as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are "unlinked" on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the "semidirect" pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell-mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation.
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12
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Use of Alefacept for Preconditioning in Multiply Transfused Pediatric Patients with Nonmalignant Diseases. Biol Blood Marrow Transplant 2015; 21:1845-52. [PMID: 26095669 DOI: 10.1016/j.bbmt.2015.06.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 06/04/2015] [Indexed: 12/20/2022]
Abstract
Transfusion-related alloimmunization is a potent barrier to the engraftment of allogeneic hematopoietic stem cells in patients with nonmalignant diseases (NMDs). Memory T cells, which drive alloimmunization, are relatively resistant to commonly used conditioning agents. Alefacept, a recombinant leukocyte function antigen-3/IgG1 fusion protein, targets CD2 and selectively depletes memory versus naive T cells. Three multiply transfused pediatric patients with NMD received a short course of high-dose i.v. alefacept (.25 mg/kg/dose on days -40 and -9 and .5 mg/kg/dose on days -33, -26, -19, and -12) before undergoing unrelated allogeneic transplant in the setting of reduced-intensity pretransplant conditioning and calcineurin inhibitor-based post-transplant graft-versus-host disease (GVHD) prophylaxis. Alefacept infusions were well tolerated in all patients. Peripheral blood flow cytometry was performed at baseline and during and after alefacept treatment. As expected, after the 5 weekly alefacept doses, each patient demonstrated selective loss of CD2(hi)/CCR7(-)/CD45RA(-) effector memory (Tem) and CD2(hi)/CCR7(+)/CD45RA(-) central memory (Tcm) CD4(+) and CD8(+) T cells with relative preservation of the CD2(lo) Tem and Tcm subpopulations. In addition, depletion of CD2(+) natural killer (NK) cells also occurred. Neutrophil recovery was rapid, and all 3 patients had 100% sorted (CD3/CD33) peripheral blood donor chimerism by day +100. Immune reconstitution (by absolute neutrophil, monocyte, and lymphocyte counts) was comparable with a cohort of historical control patients. All 3 patients developed GVHD but are all now off immune suppression and >2 years post-transplant with stable full-donor engraftment. These results suggest that alefacept at higher dosing can deplete both memory T cells and NK cells and that incorporating CD2-targeted depletion into a reduced-intensity transplant regimen is feasible and safe in heavily transfused patients.
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In Vivo Chimera Model: Creation of Primary and Secondary Chimera. Plast Reconstr Surg 2015. [DOI: 10.1007/978-1-4471-6335-0_71] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Siemionow MZ. A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries. Plast Reconstr Surg 2014. [PMID: 24263394 PMCID: PMC7121457 DOI: 10.1007/978-1-4471-6335-0_72] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population--and of the relation between age and disease--is lacking. METHODS Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words "Dupuytren," "incidence," and "prevalence." Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. RESULTS Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. CONCLUSIONS The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.
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Affiliation(s)
- Maria Z. Siemionow
- Department of Orthopaedics, University of Illinois at Chicago, Chicago, Illinois USA
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A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries. Plast Reconstr Surg 2014; 133:593-603. [PMID: 24263394 DOI: 10.1097/01.prs.0000438455.37604.0f] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population--and of the relation between age and disease--is lacking. METHODS Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words "Dupuytren," "incidence," and "prevalence." Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. RESULTS Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. CONCLUSIONS The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.
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Rogers IM. Trogocytosis in allogeneic transplants: donor cells take on the recipients identity. CHIMERISM 2013; 4:142-3. [PMID: 24121536 DOI: 10.4161/chim.26648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Trogocytosis has been identified as a mechanism of cell communication between immune cells. Unlike the more common receptor-ligand signaling, trogocytosis results in the transfer of intact and functional surface proteins between cells. For example, antigen presenting cells in contact with T cells exchange proteins which results in the T-cell acquiring antigen presentation capabilities. This allows for the newly activated T cells to stimulate other T cells thus amplifying the immune response. We have recently demonstrated that during allogeneic hematopoietic stem cell transplantation the donor cells obtain recipient MHC class I proteins by trogocytosis. The effect is a donor cell that can masquerade as a recipient cells and evade detection by NK cells and macrophages.
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Affiliation(s)
- Ian M Rogers
- Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto, ON Canada; Physiology Department; University of Toronto; Toronto, ON Canada; Obstetrics and Gynaecology Department; University of Toronto; Toronto, ON Canada
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