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Ott LC, Cuenca AG. Innate immune cellular therapeutics in transplantation. FRONTIERS IN TRANSPLANTATION 2023; 2:1067512. [PMID: 37994308 PMCID: PMC10664839 DOI: 10.3389/frtra.2023.1067512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
Successful organ transplantation provides an opportunity to extend the lives of patients with end-stage organ failure. Selectively suppressing the donor-specific alloimmune response, however, remains challenging without the continuous use of non-specific immunosuppressive medications, which have multiple adverse effects including elevated risks of infection, chronic kidney injury, cardiovascular disease, and cancer. Efforts to promote allograft tolerance have focused on manipulating the adaptive immune response, but long-term allograft survival rates remain disappointing. In recent years, the innate immune system has become an attractive therapeutic target for the prevention and treatment of transplant organ rejection. Indeed, contemporary studies demonstrate that innate immune cells participate in both the initial alloimmune response and chronic allograft rejection and undergo non-permanent functional reprogramming in a phenomenon termed "trained immunity." Several types of innate immune cells are currently under investigation as potential therapeutics in transplantation, including myeloid-derived suppressor cells, dendritic cells, regulatory macrophages, natural killer cells, and innate lymphoid cells. In this review, we discuss the features and functions of these cell types, with a focus on their role in the alloimmune response. We examine their potential application as therapeutics to prevent or treat allograft rejection, as well as challenges in their clinical translation and future directions for investigation.
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Affiliation(s)
- Leah C Ott
- Department of General Surgery, Boston Children's Hospital, Boston, MA, United States
| | - Alex G Cuenca
- Department of General Surgery, Boston Children's Hospital, Boston, MA, United States
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Lowsky R, Strober S. Establishment of Chimerism and Organ Transplant Tolerance in Laboratory Animals: Safety and Efficacy of Adaptation to Humans. Front Immunol 2022; 13:805177. [PMID: 35222384 PMCID: PMC8866443 DOI: 10.3389/fimmu.2022.805177] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 01/03/2022] [Indexed: 11/13/2022] Open
Abstract
The definition of immune tolerance to allogeneic tissue and organ transplants in laboratory animals and humans continues to be the acceptance of the donor graft, rejection of third-party grafts, and specific unresponsiveness of recipient immune cells to the donor alloantigens in the absence of immunosuppressive treatments. Actively acquired tolerance was achieved in mice more than 60 years ago by the establishment of mixed chimerism in neonatal mice. Once established, mixed chimerism was self-perpetuating and allowed for acceptance of tissue transplants in adults. Successful establishment of tolerance in humans has now been reported in several clinical trials based on the development of chimerism after combined transplantation of hematopoietic cells and an organ from the same donor. This review examines the mechanisms of organ graft acceptance after establishment of mixed chimerism (allo-tolerance) or complete chimerism (self-tolerance), and compares the development of graft versus host disease (GVHD) and graft versus tumor (GVT) activity in complete and mixed chimerism. GVHD, GVT activity, and complete chimerism are also discussed in the context of bone marrow transplantation to treat hematologic malignancies. The roles of transient versus persistent mixed chimerism in the induction and maintenance of tolerance and organ graft acceptance in animal models and clinical studies are compared. Key differences in the stability of mixed chimeras and tolerance induction in MHC matched and mismatched rodents, large laboratory animals, and humans are examined to provide insights into the safety and efficacy of translation of results of animal models to clinical trials.
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Affiliation(s)
- Robert Lowsky
- Division of Blood and Marrow Transplantation and Cancer Cellular Therapy, Stanford University School of Medicine, Stanford, CA, United States
| | - Samuel Strober
- Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, United States
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Ochando J, Ordikhani F, Jordan S, Boros P, Thomson AW. Tolerogenic dendritic cells in organ transplantation. Transpl Int 2019; 33:113-127. [PMID: 31472079 DOI: 10.1111/tri.13504] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/24/2019] [Accepted: 08/25/2019] [Indexed: 12/18/2022]
Abstract
Dendritic cells (DCs) are specialized cells of the innate immune system that are characterized by their ability to take up, process and present antigens (Ag) to effector T cells. They are derived from DC precursors produced in the bone marrow. Different DC subsets have been described according to lineage-specific transcription factors required for their development and function. Functionally, DCs are responsible for inducing Ag-specific immune responses that mediate organ transplant rejection. Consequently, to prevent anti-donor immune responses, therapeutic strategies have been directed toward the inhibition of DC activation. In addition however, an extensive body of preclinical research, using transplant models in rodents and nonhuman primates, has established a central role of DCs in the negative regulation of alloimmune responses. As a result, DCs have been employed as cell-based immunotherapy in early phase I/II clinical trials in organ transplantation. Together with in vivo targeting through use of myeloid cell-specific nanobiologics, DC manipulation represents a promising approach for the induction of transplantation tolerance. In this review, we summarize fundamental characteristics of DCs and their roles in promotion of central and peripheral tolerance. We also discuss their clinical application to promote improved long-term outcomes in organ transplantation.
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Affiliation(s)
- Jordi Ochando
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain
| | - Farideh Ordikhani
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stefan Jordan
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Peter Boros
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Angus W Thomson
- Department of Surgery and Department of Immunology, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Other Forms of Immunosuppression. KIDNEY TRANSPLANTATION - PRINCIPLES AND PRACTICE 2019. [PMCID: PMC7152196 DOI: 10.1016/b978-0-323-53186-3.00020-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Abstract
The trillions of microorganisms inhabiting human mucosal surfaces participate intricately in local homeostatic processes as well as development and function of the host immune system. These microorganisms, collectively referred to as the "microbiome," play a vital role in modulating the balance between clearance of pathogenic organisms and tolerance of commensal cells, including but not limited to human allografts. Advances in immunology, gnotobiotics, and culture-independent molecular techniques have provided growing insights into the complex relationship between the microbiome and the host, how it is modified by variables such as immunosuppressive and antimicrobial drugs, and its potential impact on posttransplantation outcomes. Here, we provide an overview of fundamental principles, recent discoveries, and clinical implications of this promising field of research.
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Prolongation of kidney allograft survival regulated by indoleamine 2, 3-dioxygenase in immature dendritic cells generated from recipient type bone marrow progenitors. Mol Immunol 2016; 79:22-31. [PMID: 27689750 DOI: 10.1016/j.molimm.2016.09.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/02/2016] [Accepted: 09/07/2016] [Indexed: 12/13/2022]
Abstract
Immature dendritic cells (iDCs) are bone marrow-derived professional antigen-presenting cells, exhibit very low levels of the co-stimulatory molecules CD80 (B7-1), CD86 (B7-2), and CD40 and major histocompatibility complex (MHC) class II and play a critical role in triggering antigen-specific immunotolerance. The enzyme indoleamine 2, 3-dioxygenase (IDO) is a cytosolic tryptophan catabolism rate-limiting step enzyme. IDO secreted by DCs shows an association with the suppression of T-cell responses and promotion of tolerance. In this study, BN rat recipients were pre-injected with donor renal alloantigen-treated recipient iDCs before kidney transplantation. The renal allograft exhibited a lighter renal rejection response, prolonged graft survival time, and an increasing content of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Additionally, up-regulated secretion of Th2 cytokines were found in recipient sera post-transplantation. Transfection of si-IDO1 RNA into renal-antigen-treated recipient iDCs reversed these changes, which suggested that IDO channel signaling may be involved in iDC-induced allograft immunotolerance. These results suggested that iDC-induced and IDO-mediated allograft immunotolerance might be a potentially feasible tactic to prolong allograft survival, in addition to immunosuppressive drugs.
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Thomson AW, Zahorchak AF, Ezzelarab MB, Butterfield LH, Lakkis FG, Metes DM. Prospective Clinical Testing of Regulatory Dendritic Cells in Organ Transplantation. Front Immunol 2016; 7:15. [PMID: 26858719 PMCID: PMC4729892 DOI: 10.3389/fimmu.2016.00015] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 01/12/2016] [Indexed: 01/03/2023] Open
Abstract
Dendritic cells (DC) are rare, professional antigen-presenting cells with ability to induce or regulate alloimmune responses. Regulatory DC (DCreg) with potential to down-modulate acute and chronic inflammatory conditions that occur in organ transplantation can be generated in vitro under a variety of conditions. Here, we provide a rationale for evaluation of DCreg therapy in clinical organ transplantation with the goal of promoting sustained, donor-specific hyporesponsiveness, while lowering the incidence and severity of rejection and reducing patients’ dependence on anti-rejection drugs. Generation of donor- or recipient-derived DCreg that suppress T cell responses and prolong transplant survival in rodents or non-human primates has been well-described. Recently, good manufacturing practice (GMP)-grade DCreg have been produced at our Institution for prospective use in human organ transplantation. We briefly review experience of regulatory immune therapy in organ transplantation and describe our experience generating and characterizing human monocyte-derived DCreg. We propose a phase I/II safety study in which the influence of donor-derived DCreg combined with conventional immunosuppression on subclinical and clinical rejection and host alloimmune responses will be examined in detail.
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Affiliation(s)
- Angus W Thomson
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Alan F Zahorchak
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine , Pittsburgh, PA , USA
| | - Mohamed B Ezzelarab
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine , Pittsburgh, PA , USA
| | - Lisa H Butterfield
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Fadi G Lakkis
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Diana M Metes
- Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Domen J, Li Y, Sun L, Simpson P, Gandy K. Rapid tolerance induction by hematopoietic progenitor cells in the absence of donor-matched lymphoid cells. Transpl Immunol 2014; 31:112-8. [PMID: 24794050 DOI: 10.1016/j.trim.2014.04.001] [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] [Received: 12/31/2013] [Accepted: 04/03/2014] [Indexed: 01/25/2023]
Abstract
BACKGROUND Donor specific hematopoietic cell transplantation has long been recognized for its potential in tolerance induction for subsequently transplanted organs. We have recently published that co-administration of Myeloid Progenitor (MP) and third party Hematopoietic Stem Cells (HSC) can induce MP-specific tolerance for subsequently transplanted organs [1]. METHODS Mice received an allogeneic HSC and third party MP transplantation simultaneous with placement of a MP-matched skin graft. Variants tested include time of graft placement, MP genotype and source of cells. RESULTS Using B10;B6-Rag2(-/-)Il2rg(-/-) mice, we demonstrate that specific tolerance can be induced by MP given simultaneous with the skin graft in the complete absence of MP-donor-matched lymphoid cells. Ex vivo expanded MP function as well as sorted cells in inducing tolerance. In addition we demonstrate that tolerance can be induced by MP in the context of autologous HSC transplantation. CONCLUSIONS Our results demonstrate that the previously observed expansion of organ donor matched Treg is not essential for tolerance, and that MP tolerance protocols can be envisioned in most clinical settings, including those involving deceased donor organs.
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Affiliation(s)
- Jos Domen
- Section of Cardiac Surgery, Children's Mercy Hospital and Clinics, Kansas City MO64108, United States; Department of Pediatrics, University of Missouri Kansas City, Kansas City, MO, United States.
| | - Yongwu Li
- Section of Cardiac Surgery, Children's Mercy Hospital and Clinics, Kansas City MO64108, United States.
| | - Lei Sun
- Section of Cardiac Surgery, Children's Mercy Hospital and Clinics, Kansas City MO64108, United States.
| | - Pippa Simpson
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States.
| | - Kimberly Gandy
- Section of Cardiac Surgery, Children's Mercy Hospital and Clinics, Kansas City MO64108, United States; Department of Pediatrics, University of Missouri Kansas City, Kansas City, MO, United States; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States.
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Dai FZ, Yang J, Chen XB, Xu MQ. Zinc finger protein A20 inhibits maturation of dendritic cells resident in rat liver allograft. J Surg Res 2013; 183:885-93. [PMID: 23481562 DOI: 10.1016/j.jss.2013.01.062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 01/20/2013] [Accepted: 01/30/2013] [Indexed: 02/05/2023]
Abstract
BACKGROUND In organ transplant field, although viewed traditionally as instigators of organ allograft rejection, donor-derived interstitial dendritic cells (DCs), including those resident in liver, or host DCs have also been implicated in transplant tolerance in experimental models. This functional dichotomy of DC is governed by various factors, the most important of which appears to be their stage of maturation. This study was designed to examine the effect of zinc finger protein A20 on maturation of DCs resident in rat liver allograft. MATERIALS AND METHODS Allogeneic (Dark Agouti [DA] rat to Lewis rat) liver transplantation was performed. Adenovirus carrying the full length of A20 was introduced into liver allografts by ex vivo perfusion via the portal vein during preservation (group A20), physiological saline (group PS), and empty Ad vector rAdEasy (group rAdEasy) that served as controls. Acute liver allograft rejection was assessed, and DCs resident in liver allografts were isolated on day 7 after transplantation. Nuclear factor kappa B (NF-κB)-binding activities, surface expression of costimulatory molecules (CD40, CD80, and CD86), expression of interleukin (IL) 12 messenger RNA (mRNA), and allocostimulatory capacity of DCs were measured with electrophoretic mobility shift assay, flow cytometry, reverse transcription-polymerase chain reaction, and mixed lymphocyte reaction (MLR), respectively. RESULTS Ex vivo transfer of A20 adenovirus by portal vein infusion resulted in overexpression of A20 protein in liver allograft after transplantation. On day 7 after transplantation, histologic examination revealed a mild rejection in group A20 but a more severe rejection in group PS and group rAdEasy. DCs from group A20 liver allografts exhibited features of immature DC with detectable but very low level of NF-κB activity, IL-12 mRNA expression, and surface expression of costimulatory molecules (CD40, CD80, and CD86), whereas DCs from group rAdEasy and group PS liver allograft displayed features of mature DC with high level of NF-κB activity, IL-12 mRNA expression, and surface expression of costimulatory molecules (CD40, CD80, and CD86). DCs from group PS and group rAdEasy liver allograft were potent inducers of DNA synthesis and interferon γ production in MLR, and DCs from group A20 liver allografts induced only minimal levels of cell proliferation and interferon γ production in MLR. CONCLUSIONS These data suggest that A20 overexpression could effectively inhibit maturation of DCs resident in liver allograft and consequently suppress acute liver allograft rejection.
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Affiliation(s)
- Fu-Zhen Dai
- Liver Transplantation Division, Department of Liver and Vascular Surgery, West China Hospital, Sichuan University, Chengdu, China
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Oh K, Kim YS, Lee DS. Maturation-resistant dendritic cells ameliorate experimental autoimmune uveoretinitis. Immune Netw 2011; 11:399-405. [PMID: 22346781 PMCID: PMC3275710 DOI: 10.4110/in.2011.11.6.399] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Revised: 11/07/2011] [Accepted: 11/11/2011] [Indexed: 01/18/2023] Open
Abstract
Background Endogenous uveitis is a chronic inflammatory eye disease of human, which frequently leads to blindness. Experimental autoimmune uveoretinitis (EAU) is an animal disease model of human endogenous uveitis and can be induced in susceptible animals by immunization with retinal antigens. EAU resembles the key immunological characteristics of human disease in that both are CD4+ T-cell mediated diseases. Dendritic cells (DCs) are specialized antigen-presenting cells that are uniquely capable of activating naïve T cells. Regulation of immune responses through modulation of DCs has thus been tried extensively. Recently our group reported that donor strain-derived immature DC pretreatment successfully controlled the adverse immune response during allogeneic transplantation. Methods EAU was induced by immunization with human interphotoreceptor retinoid-binding protein (IRBP) peptide1-20. Dendritic cells were differentiated from bone marrow in the presence of recombinant GM-CSF. Results In this study, we used paraformaldehyde-fixed bone marrow-derived DCs to maintain them in an immature state. Pretreatment with fixed immature DCs, but not fixed mature DCs, ameliorated the disease progression of EAU by inhibiting uveitogenic CD4+ T cell activation and differentiation. Conclusion Application of iBMDC prepared according to the protocol of this study would provide an important treatment modality for the autoimmune diseases and transplantation rejection.
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Affiliation(s)
- Keunhee Oh
- Laboratory of Immunology, Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
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Ezzelarab M, Thomson AW. Tolerogenic dendritic cells and their role in transplantation. Semin Immunol 2011; 23:252-63. [PMID: 21741270 DOI: 10.1016/j.smim.2011.06.007] [Citation(s) in RCA: 119] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 06/10/2011] [Indexed: 01/09/2023]
Abstract
The pursuit of clinical transplant tolerance has led to enhanced understanding of mechanisms underlying immune regulation, including the characterization of immune regulatory cells, in particular antigen-presenting cells (APC) and regulatory T cells (Treg), that may play key roles in promoting operational tolerance. Dendritic cells (DC) are highly efficient APC that have been studied extensively in rodents and humans, and more recently in non-human primates. Owing to their ability to regulate both innate and adaptive immune responses, DC are considered to play crucial roles in directing the alloimmune response towards transplant tolerance or rejection. Mechanisms via which they can promote central and peripheral tolerance include clonal deletion, the induction of Treg, and inhibition of memory T cell responses. These properties have led to the use of tolerogenic DC as a therapeutic strategy to promote organ transplant tolerance. In rodents, infusion of donor- or recipient-derived tolerogenic DC can extensively prolong donor-specific allograft survival, in association with regulation of the host T cell response. In clinical transplantation, progress has been made in monitoring DC in relation to graft outcome, including studies in operational liver transplant tolerance. Although clinical trials involving immunotherapeutic DC for patients with cancer are ongoing, implementation of human DC therapy in clinical transplantation will require assessment of various critical issues. These include cell isolation and purification techniques, source, route and timing of administration, and combination immunosuppressive therapy. With ongoing non-human primate studies focused on DC therapy, these logistics can be investigated seeking the optimal approaches. The scientific rationale for implementation of tolerogenic DC therapy to promote clinical transplant tolerance is strong. Evaluation of technical and therapeutic logistic issues is an important next step prior to the application of tolerogenic DC in clinical organ transplantation.
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Affiliation(s)
- Mohamed Ezzelarab
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST W1540, Pittsburgh, PA 15261, USA
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Kang HG, Lee JE, Yang SH, Lee SH, Gao W, Strom TB, Oh K, Lee DS, Kim YS. Donor-strain-derived immature dendritic cell pre-treatment induced hyporesponsiveness against allogeneic antigens. Immunology 2009; 129:567-77. [PMID: 20102412 DOI: 10.1111/j.1365-2567.2009.03158.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The maturation of antigen-presenting dendritic cells (DCs) serves as an important determinant for the regulation of immunity, and overall immune response. We hypothesized that a reduced immune response to donor alloantigens and improved allograft survival could be induced by pre-treating recipients with bone-marrow-derived donor-strain fixed immature DCs (FIDCs). Donor-strain-derived mature and immature DCs were fixed before grafting to ensure that they possessed a stable immunogenic phenotype. The fixed mature DCs effectively induced allogeneic T-cell proliferation in recipients, whereas FIDCs were unable to elicit an allogeneic T-cell response. T cells that had previously been exposed to FIDCs maintained naïve phenotypes and were unable to extensively divide after injection into lethally irradiated donor-strain mice. The pre-treatment of recipients with donor-strain FIDCs markedly prolonged the survival of islet as well as skin allografts. However, T-cell hyporesponsiveness induced by FIDC injection was abrogated by the depletion of CD4(+) CD25(+) T cells. Consequently, FIDC-induced T-cell hyporesponsiveness could reflect anergy rather than specific deletion. Our findings suggest that FIDCs of donor strain could be used to induce long-term graft survival.
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Affiliation(s)
- Hee Gyung Kang
- Kidney Research Institute, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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Oluwole SF, Oluwole OO, Adeyeri AO, DePaz HA. New strategies in immune tolerance induction. Cell Biochem Biophys 2009; 40:27-48. [PMID: 15289641 DOI: 10.1385/cbb:40:3:27] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Induction of tolerance in clinical organ transplantation that will obviate the use of chronic immunosuppression and preserve host immune response to other antigens remains the goal of transplant research. The thymus plays a critical role in the ability of the immune system to discriminate between self- and nonself-antigens or harmful and harmless alloantigens. We now know that multiple factors determine how the immune system responds to a self-antigen or foreign antigen. These determinants include developmental stage of the host, stage of T-cell maturity, site of antigen encounter, type and maturity of antigen-presenting cells, and presence and type of costimulatory molecules. Our understanding of the mechanisms of T-cell interactions with peptide/ major histocompatibility complex in peripheral lymphoid organs has led to experiments that translate into peripheral T-cell tolerance. The induction of high-avidity peripheral alloreactive T cells in the early phase of organ transplantation makes it difficult to achieve long-term alloantigen-specific tolerance without the use of transient perioperative immunosuppression. Therefore, protocols that induce robust tolerance in rodent and nonhuman primate models involve the use of donor antigen combined with a short course of perioperative immunosuppression. These studies suggest that the underlying mechanisms of peripheral tolerance include deletion, anergy, immune deviation, and regulatory T cells. This review focuses on recent advances in tolerance induction in experimental animal models and discusses their relevance to the development of protocols for the induction and maintenance of clinical transplant tolerance.
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Affiliation(s)
- Soji F Oluwole
- Department of Surgery, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
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Thomson AW, Robbins PD. Tolerogenic dendritic cells for autoimmune disease and transplantation. Ann Rheum Dis 2008; 67 Suppl 3:iii90-6. [PMID: 19022823 DOI: 10.1136/ard.2008.099176] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dendritic leucocytes are professional antigen-presenting cells with inherent tolerogenic properties and are regarded as critical regulators of innate and adaptive immunity. Modification of dendritic cells (DCs) in the laboratory can enhance and stabilise their tolerogenic properties. Numerous reports suggest that such immature, maturation-resistant or "alternatively activated" DCs can regulate autoreactive or alloreactive T-cell responses and promote or restore antigen-specific tolerance in experimental animal models. The first clinical testing of tolerogenic DCs in human autoimmune disease, including rheumatoid arthritis, is imminent. Herein the properties of tolerogenic DCs and prospects for their testing in chronic inflammatory disease and transplantation are reviewed.
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Affiliation(s)
- A W Thomson
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
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Ehser S, Chuang JJ, Kleist C, Sandra-Petrescu F, Iancu M, Wang D, Opelz G, Terness P. Suppressive dendritic cells as a tool for controlling allograft rejection in organ transplantation: Promises and difficulties. Hum Immunol 2008; 69:165-73. [DOI: 10.1016/j.humimm.2008.01.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2007] [Revised: 01/23/2008] [Accepted: 01/23/2008] [Indexed: 12/20/2022]
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Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 2007; 7:610-21. [PMID: 17627284 DOI: 10.1038/nri2132] [Citation(s) in RCA: 692] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
In recent years, there has been a shift from the perception of dendritic cells (DCs) solely as inducers of immune reactivity to the view that these cells are crucial regulators of immunity, which includes their ability to induce and maintain tolerance. Advances in our understanding of the phenotypical and functional plasticity of DCs, and in our ability to manipulate their development and maturation in vitro and in vivo, has provided a basis for the therapeutic harnessing of their inherent tolerogenicity. In this Review, we integrate the available information on the role of DCs in the induction of tolerance, with a focus on transplantation.
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Affiliation(s)
- Adrian E Morelli
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
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Blois SM, Kammerer U, Alba Soto C, Tometten MC, Shaikly V, Barrientos G, Jurd R, Rukavina D, Thomson AW, Klapp BF, Fernández N, Arck PC. Dendritic cells: key to fetal tolerance? Biol Reprod 2007; 77:590-8. [PMID: 17596562 DOI: 10.1095/biolreprod.107.060632] [Citation(s) in RCA: 142] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Pregnancy is a unique event in which a fetus, despite being genetically and immunologically different from the mother (a hemi-allograft), develops in the uterus. Successful pregnancy implies avoidance of rejection by the maternal immune system. Fetal and maternal immune cells come into direct contact at the decidua, which is a highly specialized mucous membrane that plays a key role in fetal tolerance. Uterine dendritic cells (DC) within the decidua have been implicated in pregnancy maintenance. DC serve as antigen-presenting cells with the unique ability to induce primary immune responses. Just as lymphocytes comprise different subsets, DC subsets have been identified that differentially control lymphocyte function. DC may also act to induce immunologic tolerance and regulation of T cell-mediated immunity. Current understanding of DC immunobiology within the context of mammalian fetal-maternal tolerance is reviewed and discussed herein.
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Affiliation(s)
- Sandra M Blois
- University Medicine of Berlin, Charité Centrum 12, Internal Medicine and Dermatology, Campus Virchow, 13353 Berlin, Germany.
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Oh BC, Lee HM, Lim DP, Cho JJ, Lee G, Lee DS, Lee JR. Effect of immature dendritic cell injection before heterotropic cardiac allograft. Transplant Proc 2007; 38:3189-92. [PMID: 17175218 DOI: 10.1016/j.transproceed.2006.10.180] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2006] [Indexed: 11/17/2022]
Abstract
Although dendritic cells (DCs) are unrivaled for initiation of immune responses, the immunomodulatory capacity of chemically fixed DC has not been thoroughly evaluated. We monitored the tolerogenic capacity of chemically fixed DCs using allogeneic heart transplantations. Bone marrow progenitors were differentiated into immature DCs which were then chemically fixed and injected intravenously into recipient mice at 14 days before allogeneic heart transplantation. Chemically fixed DCs markedly prolonged graft survival in the major histocompatibility complex (MHC) I/II mismatch cardiac transplantation (B6 --> B10.A; median survival time [MST] 12.5 days vs >70 days). T cells that encountered chemically fixed DCs showed attenuated apoptotic cell death and inactivated phenotypes after allogeneic heterotropic heart transplantation. Furthermore, when DCs from interleukin (IL)-10-/- mice were treated, the in vitro T-cell response was greater than that from IL-12-/- mice. We have suggested that the chemically fixed DCs may mediate peripheral T-cell tolerance, with therapeutic potential for allogeneic transplantation.
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Affiliation(s)
- B C Oh
- Department of Immunology, Seoul National University, Seoul, Korea
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Abstract
Dendritic cells (DCs) are uniquely well equipped antigen (Ag)-presenting cells. Their classic function was thought to be that of potent initiators of innate and adaptive immunity to infectious organisms and other Ags (including transplanted organs). Evidence has emerged, however, that DCs have a central and crucial role in determining the fate of immune responses toward either immunity or tolerance. This dichotomous function of DCs, coupled with their remarkable plasticity, renders them attractive therapeutic targets for immune modulation. In transplantation, much recent work has focused on the ability of DCs to silence immune reactivity in an Ag-specific manner in the hope of preventing rejection and diminishing reliance on potentially harmful immunosuppressive agents. Experimental strategies have included in vivo targeting of DCs, as well as ex vivo generation of regulatory (or tolerogenic) DCs with subsequent reinfusion (i.e. cell therapy). Different approaches to 'program' DC toward tolerogenic properties include genetic (transgene insertion), biologic (differential culture conditions, anti-inflammatory cytokine exposure) and pharmacologic manipulation. Recent data suggest a promising role for pharmacologic treatment as a means of generating potent regulatory DCs and have further stimulated speculation regarding their potential clinical application. Herein, we discuss evidence that the potential of regulatory DC therapy is considerable and that there are compelling reasons to evaluate it in the setting of organ transplantation in the near future.
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Affiliation(s)
- Kenneth R McCurry
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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Abstract
Dendritic cells (DCs) play a crucial role during the initiation of immune responses against non-self antigens. Following organ transplantation, activated donor- and recipient-derived DCs participate actively in graft rejection by sensitising recipient T cells via the direct or indirect pathways of allorecognition, respectively. There is increasing evidence that immature/semi-mature DCs induce antigen-specific unresponsiveness or tolerance to self antigens, both in central lymphoid tissue and in the periphery, through a variety of mechanisms (deletion, anergy and regulation). In the past few years, DC-based therapy of experimental allograft rejection has focused on ex vivo biological, pharmacological and genetic engineering of DCs to mimic/enhance their natural tolerogenicity. Successful outcomes in rodent models have built the case that DC-based therapy may provide a novel approach to transplant tolerance. Ongoing research into the role that DCs play in the induction of tolerance should allow for its clinical application in the near future.
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Affiliation(s)
- Mahyar Nouri-Shirazi
- Texas A&M University System Health Science Center, Baylor College of Dentistry, Department of Biomedical Sciences, Immunology Laboratory, 3302 Gaston Avenue, Dallas, TX 75246, USA.
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Hale DA, Dhanireddy K, Bruno D, Kirk AD. Induction of transplantation tolerance in non-human primate preclinical models. Philos Trans R Soc Lond B Biol Sci 2006; 360:1723-37. [PMID: 16147537 PMCID: PMC1569541 DOI: 10.1098/rstb.2005.1703] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Short-term outcomes following organ transplantation have improved considerably since the availability of cyclosporine ushered in the modern era of immunosuppression. In spite of this, many of the current limitations to progress in the field are directly related to the existing practice of relatively non-specific immunosuppression. These include increased risks of opportunistic infection and cancer, and toxicity associated with long-term immunosuppressive drug exposure. In addition, long-term graft loss continues to result in part from a failure to adequately control the anti-donor immune response. The development of a safe and reliable means of inducing tolerance would ameliorate these issues and improve the lives of transplant recipients, yet given the improving clinical standard of care, the translation of new therapies has become appropriately more cautious and dependent on increasingly predictive preclinical models. While convenient and easy to use, rodent tolerance models have not to date been reliably capable of predicting a therapy's potential efficacy in humans. Non-human primates possess an immune system that more closely approximates that found in humans, and have served as a more rigorous preclinical testing ground for novel therapies. Prior to clinical adaptation therefore, tolerance regimens should be vetted in non-human primates to ensure that there is sufficient potential for efficacy to justify the risk of its application.
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Affiliation(s)
- Douglas A Hale
- Digestive and Kidney Diseases, National Institute of Diabetes, NIH, Transplantation Branch, Bethesda, MD 20892, USA.
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Flores MG, Holm B, Larson MJ, Lau MK, Si MS, Lowsky R, Rousvoal G, Grumet FC, Strober S, Hoppe R, Reitz BA, Borie DC. A technique of bone marrow collection from vertebral bodies of cynomolgus macaques for transplant studies. J Surg Res 2005; 124:280-8. [PMID: 15820259 DOI: 10.1016/j.jss.2004.09.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2004] [Indexed: 01/09/2023]
Abstract
BACKGROUND Strategies to induce donor-specific allograft tolerance are best tested in preclinical models developed in nonhuman primates (NHPs). Most protocols prepare the recipient by infusing hematopoietic cells from the donor. We report here a procedure to isolate and characterize large numbers of bone marrow cells (BMCs) from cynomolgus monkeys (cynos) that can then successfully be transplanted into conditioned recipients. MATERIALS AND METHODS Vertebral columns of five cynos were excised en bloc and separated into individual vertebrae. The cancelous bone was extracted with a core puncher, fractionated, filtered, centrifuged, and resuspended in transplantation media before being analyzed by flow cytometry. In two instances, the collected BMCs were reinfused into allogeneic recipients preconditioned with a nonmyeloablative regimen. Chimerism was monitored using short-tandem repeat analysis. RESULTS The mean total BMCs yield was 25.5 x 10(9) (range of 4.00 x 10(9) to 59 x 10(9)) with mean cell viability of 93.4% (range: 90-96%). CD34+ cells and CD3+ cells averaged 0.34 and 3.91% of total BMCs, respectively. This resulted in absolute cell number yields of 1.02 x 10(8) and 1.15 x 10(9) for CD34+ and CD3+ cells, respectively. Graft-versus-host disease was absent in both bone marrow infused animals, and a maximum level of chimerism of 18% was detected at 3 weeks after BMCs infusion. CONCLUSION We present here the first detailed report of a procedure to retrieve and characterize large numbers of BMCs from vertebral bodies of cynos and demonstrate that cells collected with this technique have the capability of engrafting in allogenic recipients.
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Affiliation(s)
- Mona G Flores
- Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94305-5407, USA
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Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Prolongation of liver allograft survival by dendritic cells modified with NF-κB decoy oligodeoxynucleotides. World J Gastroenterol 2004; 10:2361-8. [PMID: 15285020 PMCID: PMC4576289 DOI: 10.3748/wjg.v10.i16.2361] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To induce the tolerance of rat liver allograft by dendritic cells (DCs) modified with NF-κB decoy oligodeoxynucleotides (ODNs).
METHODS: Bone marrow (BM)-derived DCs from SD rats were propagated in the presence of GM-CSF or GM-CSF + IL-4 to obtain immature DCs or mature DCs. GM-CSF+IL-4-propagated DCs were treated with double-strand NF-κB decoy ODNs containing two NF-κB binding sites or scrambled ODNs to ascertain whether NF-κB decoy ODNs might prevent DC maturation. GM-CSF-propagated DCs, GM-CSF + NF-κB decoy ODNs or scrambled ODNs-propagated DCs were treated with LPS for 18 h to determine whether NF-κB decoy ODNs could prevent LPS-induced IL-12 production in DCs. NF-κB binding activities, costimulatory molecule (CD40, CD80, CD86) surface expression, IL-12 protein expression and allostimulatory capacity of DCs were measured with electrophoretic mobility shift assay (EMSA), flow cytometry, Western blotting, and mixed lymphocyte reaction (MLR), respectively. GM-CSF-propagated DCs, GM-CSF + IL-4 -propagated DCs, and GM-CSF + NF-κB decoy ODNs or scrambled ODNs-propagated DCs were injected intravenously into recipient LEW rats 7 d prior to liver transplantation and immediately after liver transplantation. Histological grading of liver graft rejection was determined 7 d after liver transplantation. Expression of IL-2, IL-4 and IFN-γ mRNA in liver graft and in recipient spleen was analyzed by semiquantitative RT-PCR. Apoptosis of liver allograft-infiltrating cells was measured with TUNEL staining.
RESULTS: GM-CSF-propagated DCs, GM-CSF+NF-κB decoy ODNs-propagated DCs and GM-CSF+ scrambled ODNs-propagated DCs exhibited features of immature DCs, with similar low level of costimulatory molecule(CD40, CD80, CD86) surface expression, absence of NF-κB activation, and few allocostimulatory activities. GM-CSF + IL-4-propagated DCs displayed features of mature DCs, with high levels of costimulatory molecule (CD40, CD80, CD86) surface expression, marked NF-κB activation, and significant allocostimulatory activity. NF-κB decoy ODNs completely abrogated IL-4-induced DC maturation and allocostimulatory activity as well as LPS-induced NF-κB activation and IL-12 protein expression in DCs. GM-CSF + NF-κB decoy ODNs-propagated DCs promoted apoptosis of liver allograft-infiltrating cells within portal areas, and significantly decreased the expression of IL-2 and IFN-γ mRNA but markedly elevated IL-4 mRNA expression both in liver allograft and in recipient spleen, and consequently suppressed liver allograft rejection, and promoted liver allograft survival.
CONCLUSION: NF-κB decoy ODNs-modified DCs can prolong liver allograft survival by promoting apoptosis of graft-infiltrating cells within portal areas as well as down-regulating IL-2 and IFN-γ mRNA and up-regulating IL-4 mRNA expression both in liver graft and in recipient spleen.
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Affiliation(s)
- Ming-Qing Xu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Xu MQ, Suo YP, Gong JP, Zhang MM, Yan LN. Augmented regeneration of partial liver allograft induced by nuclear factor-kappaB decoy oligodeoxynucleotides-modified dendritic cells. World J Gastroenterol 2004; 10:573-8. [PMID: 14966919 PMCID: PMC4716982 DOI: 10.3748/wjg.v10.i4.573] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2003] [Revised: 09/06/2003] [Accepted: 09/25/2003] [Indexed: 12/15/2022] Open
Abstract
AIM To investigate the effect of NF-kappaB decoy oligodeoxynuleotides (ODNs) - modified dendritic cells (DCs) on regeneration of partial liver allograft. METHODS Bone marrow (BM)- derived DCs from SD rats were propagated in the presence of GM-CSF or GM-CSF+IL-4 to obtain immature DCs or mature DCs, respectively. GM-CSF-propagated DCs were treated with double-strand NF-kappaB decoy ODNs containing two NF-kappaB binding sites or scrambled ODNs. Allogeneic (SD rat to LEW rat) 50% partial liver transplantation was performed. Normal saline (group A), GM-CSF -propagated DCs (group B), GM-CSF+IL-4 - propagated DCs (group C), and GM-CSF+NF-kappaB decoy ODNs (group D) or scrambled ODNs -propagated DCs (group E) were injected intravenously into recipient LEW rats 7 days prior to liver transplantation and immediately after transplantation. DNA synthesis (BrdU labeling) and apoptosis of hepatocytes were detected with immunostaining and TUNEL staining postoperative 24 h, 48 h, 72 h and 84 h, respectively. Liver graft-resident NK cell activity, hepatic IFN-gamma mRNA expression and recipient serum IFN-gamma level at the time of the maximal liver allograft regeneration were measured with (51)Cr release assay, semiquantitative RT-PCR and ELISA, respectively. RESULTS Regeneration of liver allograft was markedly promoted by NF-kappaB decoy ODNs-modified immature DCs but was significantly suppressed by mature DCs, the DNA synthesis of hepatocytes peaked at postoperative 72 h in group A, group B and group E rats, whereas the DNA synthesis of hepatocytes peaked at postoperative 84 h in group C rats and 48 h in group D rats, respectively. The maximal BrdU labeling index of hepatocytes in group D rats was significantly higher than that in the other groups rats. NF-kappaB decoy ODNs-modified immature DCs markedly suppressed but mature DCs markedly promoted apoptosis of hepatocytes, liver-resident NK cell activity, hepatic IFN-gamma mRNA expression and recipient serum IFN-gamma production. At the time of the maximal regeneration of liver allograft, the minimal apoptosis of hepatocytes, the minimal activity of liver-resident NK cells, the minimal hepatic IFN-gamma mRNA expression and serum IFN-gamma production were detected in group D rats. The apoptotic index of hepatocytes, the activity of liver- resident NK cells, the hepatic IFN-gamma mRNA expression level and the serum IFN-gamma level in group D rats were significantly lower than that in the other groups rats at the time of the maximal regeneration of liver allograft. CONCLUSION The data suggest that the augmented regeneration of partial liver allograft induced by NF-kappaB decoy ODNs-modified DCs may be attributable to the reduced apoptotic hepatocytes, the suppressed activity of liver-resident NK cells and the reduced IFN-gamma production.
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Affiliation(s)
- Ming-Qing Xu
- Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Oluwole SF, Oluwole OO, Adeyeri AO, DePaz HA. New strategies in immune tolerance induction. Cell Biochem Biophys 2004. [DOI: 10.1007/bf02739010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Morelli AE, Thomson AW. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev 2003; 196:125-46. [PMID: 14617202 DOI: 10.1046/j.1600-065x.2003.00079.x] [Citation(s) in RCA: 229] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Dendritic cells (DCs) are uniquely well-equipped antigen-presenting cells (APCs) regarded classically as sentinels of the immune response, which induce and regulate T-cell reactivity. They play critical roles in central tolerance and in the maintenance of peripheral tolerance in the normal steady state. Following cell or organ transplantation, DCs present antigen to T cells via the direct or indirect pathways of allorecognition. These functions of DCs set in train the rejection response, but they also serve as potential targets for suppression of alloimmune reactivity and promotion of tolerance induction. Much evidence from various model systems now indicates that DCs can induce specific T-cell tolerance. Although underlying mechanisms have not been fully elucidated, the capacity to induce T-regulatory cells may be an important property of tolerogenic or regulatory DCs. Efforts to generate "designer" DCs with tolerogenic properties in the laboratory using specific cytokines, immunologic or pharmacologic reagents, or genetic engineering approaches have already met with some success. Alternatively, targeting of DCs in vivo (e.g. by infusion of apoptotic allogeneic cells) to take advantage of their inherent tolerogenicity has also demonstrated exciting potential. The remarkable heterogeneity and plasticity of these important APCs present additional challenges to optimizing DC-based therapies that may lead to improved tolerance-enhancing strategies in the clinic.
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Affiliation(s)
- Adrian E Morelli
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Abstract
Self-tolerance is maintained by several mechanisms including deletion (via apoptosis) and regulation. Acquired tolerance to allogeneic tissues and organs exploits similar strategies. One key difference between alloantigens and peptide antigens is the enormous number of T cells that are alloreactive. Accumulating evidence suggests that in the face of this large mass of potentially graft-destructive T cells, tolerance requires an initial wave of deletion. This creates a more level playing field in which a smaller number of regulatory T cells can then act to maintain an established tolerant state. Deletion of alloreactive T cells by apoptosis actively promotes immunoregulation as well, by interfering with proinflammatory maturation of antigen presenting cells. This article reviews the immune response to alloantigens, the development and use of both necrotic and apoptotic means of cell death during the evolution of the immune response, and the likely role and mechanisms by which apoptosis promotes, and may even be required for, transplantation tolerance.
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Affiliation(s)
- Elise Chiffoleau
- Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA
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Hancock WW, Wang L, Ye Q. Chemokine-directed dendritic cell trafficking in allograft rejection. Curr Opin Organ Transplant 2003. [DOI: 10.1097/00075200-200303000-00008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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DePaz HA, Oluwole OO, Adeyeri AO, Witkowski P, Jin MX, Hardy MA, Oluwole SF. Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival. Transplantation 2003; 75:521-8. [PMID: 12605121 DOI: 10.1097/01.tp.0000048380.84355.4a] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Because the differential polarization of T cells in response to antigen presentation is dependent on the maturational state of dendritic cells (DCs), we hypothesized that the adoptive transfer of immature myeloid DCs (iMDCs) would prolong graft survival. METHODS To evaluate this hypothesis, we studied the effects of transfer of iMDCs and mature myeloid DCs (mMDCs) on rat cardiac allograft survival. RESULTS Whereas iMDCs that do not express costimulatory molecules induce allogeneic T-cell hyporesponsiveness in coculture studies, mMDCs that express high levels of major histocompatibility complex class II costimulatory and maturation molecules induce a robust allostimulatory T-cell response. Adoptive transfer of Wistar Furth iMDCs, unlike mMDCs, 7 days before cardiac transplantation significantly prolonged graft survival. It was important that adoptive transfer of iMDCs combined with 0.5 mL antilymphocyte serum (ALS) transient immunosuppression on day -7 led to donor-specific permanent graft survival in 50% of recipients. In contrast, adoptive transfer of mMDCs combined with ALS led to graft survival similar to that in recipients treated with ALS alone. Stimulation of CD4 T cells isolated from the spleen of unresponsive allograft recipients with donor antigen resulted in donor-specific hyporesponsiveness and production of interleukin (IL)-10 and transforming growth factor-beta but not IL-4 and interferon-gamma. The tolerant T-cell unresponsiveness was reversed by the addition of IL-2. CONCLUSION Our data confirming the immunoregulatory effect of immature DCs indicate that induction of transplant tolerance by iMDCs is partly dependent on in vivo generation of regulatory T cells. This finding suggests that immunization with immature donor DCs has therapeutic potential for the induction of transplant tolerance and treatment of autoimmune diseases.
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Affiliation(s)
- Hector A DePaz
- Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
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Xu MQ, Yao ZX. Functional changes of dendritic cells derived from allogeneic partial liver graft undergoing acute rejection in rats. World J Gastroenterol 2003; 9:141-7. [PMID: 12508370 PMCID: PMC4728229 DOI: 10.3748/wjg.v9.i1.141] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate functional change of dendritic cells (DCs) derived from allogeneic partial liver graft undergoing acute rejection in rats.
METHODS: Allogeneic (SD rat to LEW rat) whole and 50% partial liver transplantation were performed. DCs from liver grafts 0 h and 4 d after transplantation were isolated and propagated in the presence of GM-CSF in vitro. Morphological characteristics of DCs propagated for 4 d and 10 d were observed by electron microscopy. Phenotypical features of DCs propagated for 10 d were analyzed by flow cytometry. Expression of IL-12 protein and IL-12 receptor mRNA in DCs propagated for 10 d was also measured by Western blotting and semiquantitative RT-PCR, respectively. Histological grading of rejection were determined.
RESULTS: Allogeneic whole liver grafts showed no features of rejection at day 4 after transplantation. In contrast, allogeneic partial liver grafts demonstrated moderate to severe rejection at day 4 after transplantation. DCs derived from allogeneic partial liver graft 4 d after transplantation exhibited typical morphological characteristics of DC after 4 d’ culture in the presence of GM-CSF. DCs from allogeneic whole liver graft 0 h and 4 d after transplantation did not exhibit typical morphological characteristics of DC until after 10 d’ culture in the presence of GM-CSF. After 10 d’ propagation in vitro, DCs derived from allogeneic whole liver graft exhibited features of immature DC, with absence of CD40, CD80 and CD86 surface expression, and low levels of IL-12 proteins (IL-12 p35 and IL-12 p40) and IL-12 receptor (IL-12Rβ1 and IL-12Rβ2) mRNA, whereas DCs from allogeneic partial liver graft 4 d after transplantation displayed features of mature DC, with high levels of CD40, CD80 and CD86 surface expression, and as a consequence, higher expression of IL-12 proteins (IL-12 p35 and IL-12 p40) and IL-12 receptors (IL-12Rβ1 and IL-12Rβ2) mRNA than those of DCs both from partial liver graft 0 h and whole liver graft 4 d after transplantation (P < 0.001) was observed.
CONCLUSION: DCs derived from allogeneic partial liver graft undergoing acute rejection display features of mature DC.
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Affiliation(s)
- Ming-Qing Xu
- Department of General Surgery, The first affiliated Hospital, Chongqing University of Medical Science, Chongqing, China.
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Coates PTH, Barratt-Boyes SM, Donnenberg AD, Morelli AE, Murphey-Corb M, Thomson AW. Strategies for preclinical evaluation of dendritic cell subsets for promotion of transplant tolerance in the nonhuman primate. Hum Immunol 2002; 63:955-65. [PMID: 12368048 DOI: 10.1016/s0198-8859(02)00457-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
A role for dendritic cells (DC) as critical regulators of immune reactivity has become increasingly recognized. There is evidence in rodent models that donor-derived DC, particularly in the immature state, can prolong organ allograft survival and even induce donor-specific tolerance. To allow the potential tolerogenic properties of these cells to be evaluated more fully with a view to clinical testing, it is necessary to identify DC subsets in nonhuman primates. We have identified the putative rhesus monkey equivalents of circulating human DC subset precursors as lineage(-), HLA-DR(+), CD123(lo),CD11c(hi)(pDC1) and lineage(-), HLA-DR(+), CD123(hi),CD11c(lo)(pDC2). Testing of these DC populations both in vitro and in vivo, as well as in transplant models in combination with conventional or experimental immunosuppressive reagents, will aid the development of novel strategies for the promotion of allo-antigen specific tolerance in transplantation.
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Affiliation(s)
- P Toby H Coates
- Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, 200 Lathrop Street, Pittsburgh, PA 15213, USA
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Hashimoto N, Narumi S, Itabashi Y, Hakamada K, Sasaki M. Efficacy of donor splenocytes mixed with bone marrow cells for induction of tolerance in sublethally irradiated mice. Transpl Immunol 2002; 10:37-41. [PMID: 12182463 DOI: 10.1016/s0966-3274(02)00020-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND High dose of bone marrow cells (BMCs) has been reported to be essential to establish donor-specific tolerance. In clinical settings, a large quantity of BMCs is very difficult to be obtained. Our previous report demonstrated that even a low dose of BMCs could establish donor-specific tolerance if mixed with splenocytes (SPLCs). In the present study, various components of SPLCs were purified or removed and were investigated their contribution for enhancement of bone marrow engraftment leading to donor-specific tolerance in sublethally irradiated mice. METHODS Sublethally irradiated C57BL/6 recipient mice were intravenously injected 3 x 10(6) BMCs mixed with various components and various numbers of SPLCs harvested from BALB/c donor mice. One week after injection, skin grafting was performed. The degree of chimerism in peripheral blood lymphocytes (PBLs) and in SPLCs was analyzed by FACS 3 months after transplantation. RESULTS Recipients receiving 3 X 106 BMCs mixed with 10 x 10(6) T cell-enriched SPLCs established chimerism. Recipients receiving BMCs mixed with macrophage-depleted SPLCs also showed chimeirism and donor-specific tolerance. B cell-enriched SPLCs did not help small dose of BMCs to establish chimerism. Irradiated SPLCs were not effective to induce tolerance even with additional infusion to recipients. CONCLUSIONS Active effects of splenic T cells were more important to help engraftment of small dose of BMCs than B cells, but the interaction between T and B cells might play some roles to enhance BMC engraftment. Splenic macrophages or dendritic cells might have some adverse effects against tolerance induction. Fatal graft-versus-host disease (GVHD) might be avoided by depleting adherent cells from SPLCs, so macrophages or dendritic cells were also considered as key components to induce donor-specific tolerance and prevent GVHD in this model.
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Affiliation(s)
- Naoki Hashimoto
- Second Department of Surgery, Hirosaki University School of Medicine, Japan.
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Ohshiro H, Yamaguchi Y, Okabe K, Takai E, Goto M, Zhang JL, Uchino S, Yamada S, Ishihara K, Furuhashi T, Mori K, Ikeda S, Sera Y, Ogawa M. Differential splenic migration of dendritic cells after immunologic unresponsiveness in rat hepatic allografts induced by pretransplant donor-specific transfusion. J Surg Res 2001; 101:29-36. [PMID: 11676551 DOI: 10.1006/jsre.2001.6228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Donor dendritic cells migrate into the recipient spleen after hepatic transplantation. We previously reported that immunologic unresponsiveness to rat hepatic allografts can be induced by prior donor-specific blood transfusion (DST). We investigated the phenotype and splenic distribution of donor dendritic cells after allografting and DST. METHODS Donor dendritic cells were identified with anti-rat dendritic cell (OX-62) and anti-donor class II MHC (RT1B(a)) (OX-76) antibodies. The phenotype of dendritic cells was determined with antibodies to CD45RC, CD62L, and the maturation markers CD80 (B7-1) and CD86 (B7-2). The cytokine profile of sorted CD45RC(+) OX-62(+) and CD45RC(-) OX-62(+) dendritic cells was analyzed by reverse transcription polymerase chain reaction (RT-PCR). RESULTS Pretransplant DST significantly prolonged rat hepatic allograft survival. Immunostaining revealed OX76(+)/OX-62(+) cells in the splenic red pulp of animals receiving pretransplant DST and in the white pulp of untreated animals after transplantation. The ratio of splenic CD45RC(-) OX-62(+) cells to CD45RC(+) OX-62(+) cells was significantly higher in DST recipients than in untreated animals. CD62L, CD80, and CD86 were lower on CD45RC(-) OX-62(+) than CD45RC(+) OX-62(+) cells. RT-PCR revealed that sorted CD45RC(-) OX-62(+) cells expressed interleukin (IL)-4 and IL-10. In contrast, sorted CD45RC(+) OX-62(+) cells expressed only IL-2 and interferon gamma (IFN-gamma). CONCLUSION Differential splenic migration of CD45RC(-) dendritic cells is associated with immunologic unresponsiveness to rat hepatic allografts.
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Affiliation(s)
- H Ohshiro
- Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan
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Abstract
Dendritic cells (DC) are professional antigen (Ag)-presenting cells considered traditionally as the passenger leukocytes that, after migration from transplanted tissues, stimulate allospecific naive T cell responses and trigger acute rejection. However, there is recent evidence that, besides their role in central T lymphocyte deletion in the thymus, DC perform a crucial function to induce/maintain peripheral T cell tolerance. This paper outlines conceptual models that try to explain how DC may induce/maintain tolerance. It also considers how such ideas have been implemented recently in an effort to generate tolerogenic DC to induce donor Ag-specific tolerance/ immunosuppression and prolonged allograft survival. These approaches include genetic engineering of donor- or recipient-derived DC to express molecules capable of promoting tolerance to alloAg.
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Affiliation(s)
- A E Morelli
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Field EH, Strober S. Tolerance, mixed chimerism and protection against graft-versus-host disease after total lymphoid irradiation. Philos Trans R Soc Lond B Biol Sci 2001; 356:739-48. [PMID: 11375076 PMCID: PMC1088460 DOI: 10.1098/rstb.2001.0851] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Total lymphoid irradiation (TLI), originally developed as a non-myeloablative treatment for Hodgkin's disease, has been adapted for the induction of immune tolerance to organ allografts in rodents, dogs and non-human primates. Moreover, pretransplantation TLI has been used in prospective studies to demonstrate the feasibility of the induction of tolerance to cadaveric kidney allografts in humans. Two types of tolerance, chimeric and non-chimeric, develop after TLI treatment of hosts depending on whether donor bone marrow cells are transplanted along with the organ allograft. An advantageous feature of TLI for combined marrow and organ transplantation is the protection against graft-versus-host disease (GVHD) and facilitation of chimerism afforded by the predominance of CD4+ NK1.1(+) -like T cells in the irradiated host lymphoid tissues. Recently, a completely post-transplantation TLI regimen has been developed resulting in stable mixed chimerism and tolerance that is enhanced by a brief course of cyclosporine. The post-transplantation protocol is suitable for clinical cadaveric kidney transplantation. This review summarizes the evolution of TLI protocols for eventual application to human clinical transplantation and discusses the mechanisms involved in the induction of mixed chimerism and protection from GVHD.
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Affiliation(s)
- E H Field
- Department of Veterans Affairs Medical Center, Iowa City, IA 52246, USA
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Takayama T, Tahara H, Thomson AW. Differential effects of myeloid dendritic cells retrovirally transduced to express mammalian or viral interleukin-10 on cytotoxic T lymphocyte and natural killer cell functions and resistance to tumor growth. Transplantation 2001; 71:1334-40. [PMID: 11397973 DOI: 10.1097/00007890-200105150-00027] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Genetic engineering of dendritic cells (DC) to express immunosuppressive molecule(s) offers potential for therapy of allograft rejection and autoimmune disease. Viral (v) interleukin (IL)-10, encoded by the Epstein-Barr virus, is highly homologous to mammalian (m) IL-10, but lacks certain of its T-cell stimulatory activities. Our aim was to evaluate and compare the influence of vIL-10 and mIL-10 gene transfer on the T-cell and natural killer (NK) cell stimulatory activity of DC, and their impact on the growth of transplantable tumors. METHODS Myeloid DC progenitors, propagated from the bone marrow of C57BL/6J (H2b) mice in granulocyte-macrophage colony-stimulating factor + IL-4, were transduced using retroviral supematant from the BOSC ecotropic packaging cell line. The function of the IL-b gene-modified DC was assessed by examining their ability to induce naive allogeneic T-cell proliferation and cytotoxic T lymphocyte (CTL) generation. MCA205 (H2b) sarcoma cells mixed with either vIL-10-, mIL-10-, or Zeo (control gene)-transduced DC were inoculated intradermally into C57BL/6J (syngeneic) or BALB/cJ (H2d) (allogeneic) recipients, which were monitored for tumor growth. The role of specific host effector cell populations in tumor resistance was determined by antibody depletion. RESULTS Compared with control gene-modified DC, both vIL-10- and mIL-10-transduced DC, which secreted the transgene product, showed reduced surface expression of MHC class II and costimulatory molecules, and impaired ability to induce T-cell proliferation. vIL-10-transduced DC were also inhibited with respect to CTL induction but did not affect the generation of NK cells. By contrast, mIL-10-transduced DC augmented CTL generation and NK cell activity. In the tumor transplant model, vIL-10-transduced DC enhanced tumor growth both in syngeneic and allogeneic hosts, whereas mIL-10-transduced cells inhibited tumor development. Depletion of CD4+ or CD8+ T cells or NK cells in mice given mIL-10-transduced DC reversed this therapeutic effect. CONCLUSION mIL-10 gene-modified myeloid DC promote CTL and NK cell-mediated responses and inhibit tumor growth. By contrast, vIL-10-engineered DC, which elicit diminished CTL responses and do not promote NK cell activity, seem to have therapeutic potential for inhibition of T cell-mediated immunity.
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Affiliation(s)
- T Takayama
- Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA
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39
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Wang Y, Goldschneider I, O’Rourke J, Cone RE. Blood mononuclear cells induce regulatory NK T thymocytes in anterior chamber‐associated immune deviation. J Leukoc Biol 2001. [DOI: 10.1189/jlb.69.5.741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Yafei Wang
- Department of Pathology, Farmington
- Vision Immunology Center, University of Connecticut Health Center, Farmington
| | | | - James O’Rourke
- Department of Pathology, Farmington
- Vision Immunology Center, University of Connecticut Health Center, Farmington
| | - Robert E. Cone
- Department of Pathology, Farmington
- Vision Immunology Center, University of Connecticut Health Center, Farmington
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Hayamizu K, Shinozaki K, Fan X, Yahata H, Tashiro H, Asahara T. IL-10 transduction of liver allografts induces antiinflammatory monocytes in long-term-surviving hosts. Transplant Proc 2001; 33:355. [PMID: 11266858 DOI: 10.1016/s0041-1345(00)02045-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- K Hayamizu
- Department of Surgery II, Hiroshima University Faculty of Medicine, Hiroshima, Japan
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41
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Mathew JM, Fuller L, Carreno M, Garcia-Morales R, Burke GW, Ricordi C, Esquenazi V, Tzakis AG, Miller J. Involvement of multiple subpopulations of human bone marrow cells in the regulation of allogeneic cellular immune responses. Transplantation 2000; 70:1752-60. [PMID: 11152108 DOI: 10.1097/00007890-200012270-00015] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND The identity of the cells in the human bone marrow that function as effective regulators of in vitro and possibly in vivo cellular immune responses is not well established. METHODS Cell subpopulations were isolated from cadaver donor vertebral-body bone marrow cells (DBMC) by using immuno-magnetic microbeads and were tested as inhibitors (modulators) in cell-mediated lympholysis (CML) and mixed lymphocyte reaction (MLR) responses of normal peripheral blood lymphocytes stimulated with irradiated cadaver donor spleen cells. RESULTS Compared with spleen cells as controls, un-irradiated T-cell depleted DBMC inhibited both the MLR and CML responses of allogeneic responder cells in a dose dependent manner (as in our previous reports). The inhibition was also mediated by a number of purified subpopulations including pluripotent CD34+ stem cells, and their CD34 negative early progeny of both lymphoid and myeloid lineages. These included DBMC enriched for non-T-cell lymphoid precursors (NT-LP/DBMC; i.e., DBMC depleted of CD3, CD15, and glycophorin-A positive cells) and DBMC positively selected for CD38+, CD2+, CD5+, and CD1+ lymphoid cells (all were depleted of CD3+ cells) as well as CD33+ (but CD15 negative) myeloid precursors. However, positively selected CD19+ B-cells and CD15+ myeloid cells did not inhibit the MLR and CML responses. The NT-LP/DBMC that had been repeatedly stimulated with irradiated allogeneic peripheral blood lymphocytes caused the strongest inhibition of the MLR and CML responses of the same allogeneic cells with 200 times fewer modulator cells needed than uncultured DBMC (P<0.001). Flow cytometric analysis revealed that majority of cells in these cell lines had become CD3+ TcR-alphabeta+ CD4+ and CD28+ cells. CONCLUSION A variety of less differentiated cells of various lineages residing in the human bone marrow are immunoregulatory in vitro. Among them, there is at least one subset that can undergo differentiation in vitro into regulatory T cells that can be maintained in long-term cultures.
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Affiliation(s)
- J M Mathew
- Department of Surgery, University of Miami School of Medicine, and The Miami Veterans Affairs Medical Center, Florida 33136, USA.
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42
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Liang J, Yamaguchi Y, Matsuda T, Ohshiro H, Zhang JL, Okabe K, Matsumura F, Ishihara K, Uchino S, Mori K, Yamada S, Ogawa M. Posttransplant infusion of donor-specific blood induces immunological unresponsiveness in rat hepatic allografts. Transplantation 2000; 70:1363-71. [PMID: 11087154 DOI: 10.1097/00007890-200011150-00017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND We previously reported that pretransplant donor-specific blood transfusion (DST) induces CD45RC-CD4+ T cells, Th2-like effector cells, and prolongs rat hepatic allograft survival. Our study investigated the effects of posttransplant DST on rat hepatic allograft survival. METHODS Three days after transplantation, LEW (RT1(1)) recipient rats with ACI (RT1a) livers were injected i.v. with freshly heparinized donor-specific blood. The time kinetics of CD45RC-CD4+ and CD45RC+CD4+ T cell subsets in hepatic infiltrates were examined. RESULTS Posttransplant DST significantly prolonged rat hepatic allograft survival. Interferon (IFN)-gamma, interleukin (IL)-12, and IL-18 mRNA levels in hepatic allografts of untreated recipients were significantly greater than in recipients treated with posttransplant DST. However, hepatic allografts of recipients treated with posttransplant DST showed significantly higher IL-4, IL-10, and transforming growth factor (TGF)-beta mRNA levels than untreated recipients. The ratio of CD45RC-CD4+ T cells to CD45RC+CD4+ T cells was significantly higher in hepatic allografts treated with posttransplant DST than in untreated animals. Immunostaining with anti-rat dendritic cell (OX-62) monoclonal antibody revealed that OX-62+ cells were distributed to the splenic red pulp of animals treated with posttransplant DST and to the splenic white pulp in untreated animals. Most OX62+ cells isolated from the spleen of recipients treated with posttransplant DST expressed donor RT1Ba class II major histocompatibility complex antigens, suggesting that OX-62+ cells were of donor origin. CONCLUSION Posttransplant DST was associated with persistent infiltration of CD45RC-CD4+ T cells, Th2-like effector cells, in rat hepatic allografts, causing immunologic unresponsiveness and establishment of microchimerism in the spleen.
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Affiliation(s)
- J Liang
- Department of Surgery II, Kumamoto University Medical School, Japan
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43
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Hayamizu K, Yahata H, Shinozaki K, Tanji H, Strober S, Asahara T. Granulocyte colony-stimulating factor-mobilized donor monocytes facilitate heart allograft acceptance. Transplant Proc 2000; 32:2068-9. [PMID: 11120070 DOI: 10.1016/s0041-1345(00)01561-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- K Hayamizu
- Department of Surgery II, Hiroshima University Faculty of Medicine, and Division of Clinical Radiology, Hiroshima University Medical Hospital, Hiroshima, Japan.
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44
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Hirano A, Luke PP, Specht SM, Fraser MO, Takayama T, Lu L, Hoffman R, Thomson AW, Jordan ML. Graft hyporeactivity induced by immature donor-derived dendritic cells. Transpl Immunol 2000; 8:161-8. [PMID: 11147696 DOI: 10.1016/s0966-3274(00)00022-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Immature dendritic cells (DCs) are deficient in surface co-stimulatory molecules and have been shown to exhibit a 'tolerogenic' potential. We investigated the allostimulatory activity of immature DCs in one-way mixed leukocyte reactions and their capacity to inhibit anti-donor cytolytic activity in the sponge matrix allograft model. Immature DCs (CD80 and CD86 deficient) were derived from bone marrow cells propagated in GM-CSF and TGF-beta1. Mature DCs (CD80+ and CD86+) were derived from bone marrow cells propagated in GM-CSF and IL-4. Either 2 x 10(6) DBA/2J (DBA, H-2d) immature DCs or 2 x 10(6) mature DCs were injected intravenously into C57BL/6J (B6, H-2b) mice 7 days prior to sponge matrix allograft implantation. On day 12, the sponge was harvested and the graft-infiltrating cells were tested in vitro for cytotoxic T lymphocyte (CTL) activity. Immature dendritic cell (DC) infused significantly and markedly inhibited intra-graft CTL activity compared to mature DCs and syngeneic bone marrow control cells. The administration of immature DCs directly into the sponge allograft failed to induce hyporeactivity. Thus, the only systemic infusion of immature donor DCs was able to recapitulate the donor-specific transfusion effect, and the capacity of donor bone marrow cells to induce donor-specific hyporeactivity in the sponge allograft model.
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Affiliation(s)
- A Hirano
- Department of Urology, University of Pittsburgh Medical Center and Veterans Administration Medical Center, PA, USA
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45
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Abstract
Graft-derived 'passenger' dendritic cells have been classically considered as the instigators of acute organ rejection. However, recent advances have revealed that dendritic cells are also involved in the induction/maintenance of peripheral tolerance. This paper briefly reviews the most recent knowledge of the role of donor and recipient dendritic cells during the immune response against allografts, and of the clinical potential of 'tolerogenic' dendritic cells.
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Affiliation(s)
- A E Morelli
- Thomas E Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, PA 15213, USA.
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46
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Abstract
The past year has witnessed the resolution of some long-standing enigmas surrounding the immunobiology of dendritic cells, illuminating their opposing roles in peripheral tolerance and allograft rejection. Nevertheless these advances have posed many new questions, the answers to which may subtly influence our approach to the treatment of rejection while bringing ever closer the prospect of donor-specific transplanation tolerance.
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Affiliation(s)
- P J Fairchild
- Sir William Dunn School of Pathology, University of Oxford, UK.
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47
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Lee WC, Qiani S, Wan Y, Li W, Xing Z, Gauldie J, Fung JJ, Thomson AW, Lu L. Contrasting effects of myeloid dendritic cells transduced with an adenoviral vector encoding interleukin-10 on organ allograft and tumour rejection. Immunology 2000; 101:233-41. [PMID: 11012777 PMCID: PMC2327075 DOI: 10.1046/j.1365-2567.2000.00096.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Mouse bone marrow-derived myeloid dendritic cells (DC) propagated in granulocyte-macrophage colony-stimulating factor and transforming growth factor-beta1 (TGF-beta1) (so-called 'TGF-beta DC') are phenotypically immature, and prolong allograft survival. Interleukin-10 (IL-10) has been shown to inhibit the maturation of DC by down-regulating surface major histocompatibility complex (MHC) class II, co-stimulatory and adhesion molecule expression. Genetic engineering of TGF-beta DC to overexpress IL-10 might enhance their tolerogenic potential. In this study, adenoviral (Ad) vectors encoding the mouse IL-10 gene were transduced into B10 (H2b) TGF-beta DC. Transduction with Ad-IL-10 at a multiplicity of infection (MOI) of 50-100 resulted in a modest reduction in the incidence of DC expressing surface MHC class II, CD40, CD80 and CD86. Paradoxically, Ad-IL-10 transduction enhanced the allostimulatory activity of DC in mixed leucocyte reactions and cytotoxic T lymphocyte assays, and increased their natural killer cell stimulatory activity. Systemic injection of normal C3H recipients with Ad-IL-10-transduced B10-DC 7 days before organ transplantation, exacerbated heart graft rejection and augmented circulating anti-donor alloantibody titres. Contrasting effects were observed in relation to tumour growth. All mice preimmunized with Ad-IL-10-transduced, tumour antigen (B16F10)-pulsed DC developed palpable tumours, associated with significant inhibition of splenic anti-tumour cytotoxic T lymphocyte generation. Animals pretreated with control Ad-LacZ-transduced, B16F10-pulsed DC however, remained tumour free. These findings are consistent with the multifunctional immunomodulatory properties of mammalian IL-10.
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MESH Headings
- Adenoviruses, Human/genetics
- Animals
- Cytotoxicity, Immunologic
- Dendritic Cells/immunology
- Genetic Vectors
- Graft Rejection/immunology
- Heart Transplantation/immunology
- Isoantibodies/biosynthesis
- Killer Cells, Natural/immunology
- Lymphocyte Culture Test, Mixed
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Myeloid Cells/immunology
- Neoplasm Transplantation
- Neoplasms, Experimental/immunology
- Neoplasms, Experimental/prevention & control
- Spleen/immunology
- Transforming Growth Factor beta/metabolism
- Tumor Cells, Cultured
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Affiliation(s)
- W C Lee
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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48
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Takayama T, Morelli AE, Robbins PD, Tahara H, Thomson AW. Feasibility of CTLA4Ig gene delivery and expression in vivo using retrovirally transduced myeloid dendritic cells that induce alloantigen-specific T cell anergy in vitro. Gene Ther 2000; 7:1265-73. [PMID: 10918497 DOI: 10.1038/sj.gt.3301244] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Dendritic cells (DC) are highly specialised, bone marrow (BM)-derived antigen-presenting cells (APC) that initiate and regulate immune responses. They provide costimulatory signals (in particular, CD40 and the CD28 ligands CD80 and CD86) necessary for naive T cell activation. Functional expression of CD80 and CD86 is blocked by the fusion protein cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4Ig), that promotes tolerance induction in animals. Here, replicating mouse (B10; H2b) myeloid DC progenitors, were retrovirally transduced to express CTLA4Ig using the centrifugal enhancement method. Gene product was detected by immunocyto- or histochemistry. Maximal DC transduction efficiency was 62%. Compared with control, zeomycin-resistance gene (Zeo)-transduced DC, CTLA4Ig-expressing cells showed markedly impaired capacity to stimulate naive allogeneic (C3H; H2k) T cell proliferation and cytotoxic T lymphocyte (CTL) generation. Their ability to induce alloantigen-specific T cell hyporesponsiveness was reversed by exogenous IL-2 in secondary mixed leukocyte reactions (MLR). Following local (s.c.) transfer to allogeneic recipients, the genetically modified DC trafficked to T cell areas of draining lymphoid tissue, where transgene expression was detected. Ex vivo analysis of proliferative and CTL responses revealed donor-specific inhibition of alloimmune reactivity by the CTLA4Ig-transduced DC. This effect was associated with marked inhibition of interferon (IFN)-gamma production, but significant augmentation of IL-4 and IL-10 secretion. Thus, retroviral transduction of DC permits in vivo delivery of CTLA4Ig to the precise microenvironment where antigen (Ag) presentation occurs. Comparatively nonimmunogenic retroviral vectors, that allow permanent transgene expression in DC, and promote localized delivery of the immunosuppressive transgene product, promote immune deviation and Ag-specific T cell hyporesponsiveness.
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Affiliation(s)
- T Takayama
- Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15213, USA
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49
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Morelli AE, Antonysamy MA, Takayama T, Hackstein H, Chen Z, Qian S, Zurowski NB, Thomson AW. Microchimerism, donor dendritic cells, and alloimmune reactivity in recipients of Flt3 ligand-mobilized hemopoietic cells: modulation by tacrolimus. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2000; 165:226-37. [PMID: 10861056 DOI: 10.4049/jimmunol.165.1.226] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Flt3 ligand (FL) is a potent hemopoietic growth factor that strikingly enhances stem cells and dendritic cells (DC) in vivo. We examined the impact of infusing FL-mobilized bone marrow (BM) cells on microchimerism and anti-donor reactivity in normal and tacrolimus-immunosuppressed, noncytoablated allogeneic recipients. BM from B10 (H2b) mice given FL (10 microg/day; days 0-8; FL-BM) contained a 7-fold higher incidence of potentially tolerogenic immature CD11c+ DC (CD40low, CD80low, CD86low, MHC IIlow) that induced alloantigen-specific T cell hyporesponsiveness in vitro. C3H (H2k) mice received 50 x 106 normal or FL-BM cells (day 0) and tacrolimus (2 mg/kg/day; days 0-12). On day 15, enhanced numbers of donor (IAb+) cells were detected in the thymi and spleens of FL-BM recipients. Tacrolimus markedly enhanced microchimerism, which declined as a function of time. Ex vivo splenocyte proliferative and CTL responses and Th1 cytokine (IFN-gamma) production in response to donor alloantigens were augmented by FL-BM infusion, but reduced by tacrolimus. Systemic infusion of purified FL-BM immature DC, equivalent in number to that in corresponding whole BM, confirmed their capacity to sensitize, rather than tolerize, recipient T cells in vivo. In vitro, tacrolimus suppressed GM-CSF-stimulated growth of myeloid DC from normal BM much more effectively than from FL-BM without affecting MHC class II or costimulatory molecule expression. Infusion of normal B10 BM cells at the time of transplant prolonged C3H heart allograft survival, whereas FL-BM cells did not. A therapeutic effect of tacrolimus on graft survival was observed in combination with normal, but not FL-BM cells. These findings suggest the need for alternative immunosuppressive strategies to calcineurin inhibition to enable the engraftment, survival, and immunomodulatory function of FL-enhanced, immature donor DC.
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MESH Headings
- Adjuvants, Immunologic/administration & dosage
- Adjuvants, Immunologic/pharmacology
- Animals
- Bone Marrow Transplantation/immunology
- Cell Differentiation/drug effects
- Cell Differentiation/immunology
- Cell Separation
- Cells, Cultured
- Cytotoxicity, Immunologic/drug effects
- Dendritic Cells/cytology
- Dendritic Cells/drug effects
- Dendritic Cells/metabolism
- Dendritic Cells/transplantation
- Drug Administration Schedule
- Drug Combinations
- Epitopes, T-Lymphocyte/immunology
- Graft Survival/drug effects
- Heart Transplantation/immunology
- Hematopoietic Stem Cell Mobilization
- Hematopoietic Stem Cell Transplantation
- Histocompatibility Antigens Class II/biosynthesis
- Immunosuppressive Agents/administration & dosage
- Infusions, Intravenous
- Injections, Intraperitoneal
- Isoantigens/immunology
- Ligands
- Lymphocyte Activation/drug effects
- Lymphocyte Activation/immunology
- Lymphocyte Culture Test, Mixed
- Lymphocyte Depletion
- Lymphoid Tissue/cytology
- Lymphoid Tissue/immunology
- Lymphoid Tissue/metabolism
- Male
- Membrane Proteins/administration & dosage
- Membrane Proteins/immunology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C3H
- Mice, Inbred C57BL
- Radiation Chimera/immunology
- Spleen/cytology
- Spleen/immunology
- Spleen/metabolism
- T-Lymphocytes/drug effects
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Tacrolimus/administration & dosage
- Tacrolimus/pharmacology
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Affiliation(s)
- A E Morelli
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, PA 15213, USA
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50
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Morelli AE, O'Connell PJ, Khanna A, Logar AJ, Lu L, Thomson AW. Preferential induction of Th1 responses by functionally mature hepatic (CD8alpha- and CD8alpha+) dendritic cells: association with conversion from liver transplant tolerance to acute rejection. Transplantation 2000; 69:2647-57. [PMID: 10910289 DOI: 10.1097/00007890-200006270-00027] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Liver grafts are accepted across major histocompatibility barriers in mice without immunosuppressive therapy. Potentially tolerogenic immature donor dendritic cells (DC) may play a key role in this phenomenon, but recovery of purified DC from normal livers for functional analysis is inherently difficult. Administration of in vitro propagated immature donor DC to recipients of different types of allograft can prolong transplant survival. By contrast, marked increases in donor liver DC as the result of Flt3 ligand (FL) administration and the resulting augmentation of allostimulatory activity within host lymphoid tissue, is associated with acute graft rejection. Here, we compared the capacity of in vitro generated normal liver immature DC and FL-treated donor liver DC to induce alloimmune CD4+ T helper (Th) 1/Th2 and CD8+ T cytotoxic (Tc) 1/Tc2 responses, in vitro and in vivo. METHODS B10 (H2b, IAb) immature liver DC were propagated from normal hepatic nonparenchymal cells in granulocyte macrophage-colony stimulating factor (GM-CSF) for 6-8 days. Freshly isolated DC from livers of FL-treated mice (FL-liver DC) were cultured overnight (o/n) in GM-CSF, and both myeloid (CD11c+ CD8alpha-) and lymphoid DC (CD11c+ CD8alpha+) flow-sorted for functional analysis. Proliferative activity and production of interferon (IFN)-gamma, interleukin (IL)-4, and IL-10 by naive C3H (H2k, IEk) T cells in response to DC stimulation was assessed by [3H]thymidine incorporation, and by multicolor flow cytometric analysis, respectively, after 3-day mixed leukocyte reactions. To investigate their in vivo trafficking, B10 DC were injected subcutaneously into normal C3H mice. Sections of lymphoid tissue were immunostained for donor MHC class II+ (IAb+) cells, and for IFN-gamma, IL-4, and IL-10 production. Donor cells and clusters of specific cytokine-secreting cells were enumerated. RESULTS Both in vitro propagated normal liver-derived DC, and freshly isolated bulk FL-liver DC showed an immature phenotype (MHC class II(lo), CD40-, CD80-, and CD86-) and were weak stimulators of naive allogeneic T cells. After o/n incubation in GM-CSF, both CD8alpha- and CD8alpha+ FL-liver DC exhibited marked up-regulation of surface MHC class II and costimulatory molecules, and acquired potent stimulatory activity for Th1 (mainly) and Th2 cells. Both in vitro propagated immature DC and o/n-cultured mature FL-liver DC homed in vivo to host lymphoid tissues, but with different kinetics. Whereas the mature allogeneic FL-liver DC induced IFN-gamma+ clusters in splenic T-cell areas within 2 days, the IFN-gamma response to immature DC was much slower and weaker. CONCLUSIONS FL-treated donor livers that are rejected acutely contain markedly enhanced numbers of myeloid (CD8alpha-) and lymphoid (CD8alpha+) DC, many of which are capable of maturing rapidly into strong inducers of Th1 and Tcl responses. Substantial differences in quantity, and both the phenotypic and functional characteristics of the DC constituency of donor livers, may contribute significantly toward the distinct outcomes of liver transplant tolerance and rejection.
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Affiliation(s)
- A E Morelli
- Thomas E Starzl Transplantation Institute, and Department of Surgery, University of Pittsburgh, Pennsylvania, USA
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