- Email: [email protected]
Advances in transplantation
Seminars in Immunology 23 (2011) 222–223
Contents lists available at SciVerse ScienceDirect
Seminars in Immunology journal homepage: www.elsevier.com/locate/ysmim
Editorial
Advances in transplantation
Transplantation is recognized as one of the major medical achievements over the last half century and in most cases the only available therapeutic option for saving the lives of patients with end stage organ failure [1]. Despite outstanding short term graft and patient survival rates, solid organ transplantation continues to face several major challenges including a severe shortage of donor grafts, poor long term graft survival resulting from chronic vascular rejection and major side effects from the need for long term immunosuppressive therapy required for the prevention of rejection [2,3]. The introduction of calcineurin inhibitors (CNI) in the 1980s substantially reduced the incidence and severity of acute graft rejection and improved rates of early engraftment [4]. Although a number of new immunosuppressive agents have been introduced over the past twenty years, this has not markedly affected patient and graft outcomes. In more recent years, immunosuppressive strategies have evolved to reduce long term toxicity and improve graft function, at least in the first few years posttransplant [5,6]. Despite these improvements, patients still depend on the use of non-specific immunosuppression, with it risk of complications, including life-threatening infections, accelerated cardiovascular disease, diabetes and cancer. Moreover, late graft loss, due in large part to chronic rejection, remains an intractable problem. Recognition of the pathogenic role of donor specific antibodies especially in renal, heart and lung transplant recipients has prompted the development of strategies to target B cells, plasma cells and other components of the humoral immune system. The importance of co-stimulatory pathways to allo-recognition and rejection has led to the development of the immunosuppressive agent belatacept to block T cell co-stimulation through CD28 [7,8]. Belatacept has recently been approved by the FDA for recipients of kidney transplants and its use may allow for CNI free immunosuppression with the hope of reduced long term renal and cardiovascular toxicity with no increase in the incidence of allograft rejection. Induction of tolerance in transplant patients would allow for elimination/avoidance of toxic immunosuppressive agents. Strategies that have shown the potential for tolerance in animal models, but not yet in non-human primates or humans, include the combination of co-stimulatory blockade and T cell depletion as well as expansion of antigen specific Treg. Tolerance has been achieved in some HLA mismatched kidney allograft recipients following induction of transient mixed chimerism using donor bone marrow transplantation and a non myeloablative conditioning regimen [9,10]. Technical advances in flow cytometry, antigen specific lymphocyte assays and genome wide analysis have led to the development of powerful immune-monitoring techniques to characterize allo immune responses. It is hoped that these 1044-5323/$ – see front matter © 2011 Published by Elsevier Ltd. doi:10.1016/j.smim.2011.08.013
may eventually allow elimination of dependence on histologic examination of grafts (biopsies) for detection of rejection [11]. Furthermore, molecular or cell based biomarkers are emerging which may be useful to monitor the immune status of the patient. It is hoped that these will detect rejection or immune events before the transplanted organ is damaged. Additionally, patterns of genomic biomarkers are emerging which may predict patients who have achieved tolerance. The ultimate goal of these studies is to identify markers with sufficient predictive value to allow for successful discontinuation of immunotherapy. In this volume of Seminars in Immunology, we have invited experts in basic immunology and transplantation to discuss advances which might be highly relevant to advancing solid organ transplantation. In most instances we invited experts from two different institutions to discuss advances in their respective fields, focusing on controversies, so that differencing perspectives could be synthesized for the reader. Dr F. Lakkis discusses how the innate immune system recognizes non-microbial non-self such as transplant antigens. He describes the principal mechanisms of non-self or damaged self recognition by the innate immune system, including the role of pattern recognition receptors and the danger hypothesis. Wekerle and Sayegh provide an update on the effects of disrupting T cell costimulation on the allo response. They discuss the positive signals involved in T cell activation and described how negative signals inhibit T cell activation and promote tolerance. They discuss the evolution of these concepts for development of co-stimulatory pathways as therapeutic targets for organ transplantation. It is now appreciated that the humoral immune system is a significant barrier to solid organ transplantation due to antibody-mediated recognition of non-self proteins and carbohydrates expressed on transplanted organs. Although the presence of these antibodies was previously considered to be a contraindication to transplantation, Montogomery and colleagues provide data on new ways of testing for these antibodies and on therapeutic strategies that have now made it possible to successfully cross certain antibody barriers. The ability of dendritic cells (DC) to regulate both innate and adaptive immune responses suggests an approach to directing alloimmune responses towards transplant tolerance and away from rejection. Angus Thomson and colleagues provide important new information on the use of DC in tolerogenic strategies in clinical transplantation, including source, isolation and purification techniques, route and timing of administration and combination with immunosuppressive therapy. Many types of regulatory T cells are thought to maintain selftolerance and control of immune responses to foreign antigens. In the article by Shalev et al. the major regulatory T cell subsets
Editorial / Seminars in Immunology 23 (2011) 222–223
described over the past decade and their role in transplantation are discussed with special emphasis on CD4+ CD25+ FoxP3+ regulatory T cells. They discuss proposed mechanisms for their suppressive activity, including generation of inhibitory cytokines, induced death or perturbation of effector cells mediated by changes in extracellular nucleotide/nucleoside fluxes with alterations in intracellular signaling molecules, including cyclic AMP, and inhibition of DC function. Levings and Wood review mechanisms in which Treg could be manipulated or expanded in vivo and the potential of in vitro expanded/generated Treg for cellular therapy. Strober et al. define how novel allogeneic hematopoietic cell transplantation (HCT) approaches have been used to treat hematologic mechanisms and the potential of these reduced toxicity regimens to be useful for organ allograft tolerance induction. They review two successful approaches to HCT that involved reduced intensity conditioning regimens that were associated with improvements in safety in patients with hematologic malignancies, even in the challenging setting of full HLA haplotype mismatch. They discuss how these strategies have been successfully applied for induction of organ allograft tolerance in humans. Advances in gene profiling, sequencing, proteomics and bioinformatics now herald the potential for personalized monitoring and therapeutics in the field of transplantation, with the hope of improving graft survival and reducing patient morbidity from overimmunosuppression. In their article, Salomon and Sarwal summarize the current status of potentially useful technologies available for genomics and proteomics in transplantation, defining the challenges facing their clinical application. Successful adoption of these technologies would usher in a new age of patient care by replacing non specific, invasive techniques with noninvasive, effective and specific tests for patients undergoing solid organ transplantation. We believe that the major advances in our understanding of the immunology of rejection and development of tolerance offers the hope that in the very near future patients will be treated post-transplant with personalized approaches to immunosuppression. Furthermore, we also believe that tolerance will ultimately be achievable in many transplant patients, allowing transplantation without the need for long-term immunosuppression.
223
References [1] Levy GA. Progress in transplantation. Therapeutic Drug Monitoring 2010;32:246–9. [2] Sayegh MH, Carpenter CB. Transplantation 50 years later—progress, challenges, and promises. The New England Journal of Medicine 2004;351:2761–6. [3] Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. The New England Journal of Medicine 2002;346:580–90. [4] Hong JC, Kahan BD. Immunosuppressive agents in organ transplantation: past, present, and future. Seminars in Nephrology 2000;20:108–25. [5] Selzner N, Grant DR, Shalev I, Levy GA. The immunosuppressive pipeline: meeting unmet needs in liver transplantation. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2010;16:1359–72. [6] Vincenti F. What’s in the pipeline? New immunosuppressive drugs in transplantation. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2002;2:898–903. [7] Larsen CP, Grinyo J, Medina-Pestana J, Vanrenterghem Y, Vincenti F, Breshahan B, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation 2010;90:1528–35. [8] Wojciechowski D, Vincenti F. How the development of new biological agents may help minimize immunosuppression in kidney transplantation: the impact of belatacept. Current Opinion in Organ Transplantation 2010 [epub ahead of print]. [9] Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. The New England Journal of Medicine 2008;358:362–8. [10] Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. The New England Journal of Medicine 2008;358:353–61. [11] Naesens M, Sarwal MM. Molecular diagnostics in transplantation. Nature Reviews Nephrology 2010;6:614–28.
Megan Sykes Columbia Center for Translational Immunology, Columbia University Medical Center, 650 West 168th Street, BB 1512, New York, NY, United States Gary Levy ∗ University of Toronto Transplant Institute, Toronto General Hospital, NCSB 11-1236, 585 University Avenue, Toronto, Ontario, Canada M5G 2N2 ∗ Corresponding author. E-mail addresses: [email protected] (M. Sykes), [email protected] (G. Levy)
Contents lists available at SciVerse ScienceDirect
Seminars in Immunology journal homepage: www.elsevier.com/locate/ysmim
Editorial
Advances in transplantation
Transplantation is recognized as one of the major medical achievements over the last half century and in most cases the only available therapeutic option for saving the lives of patients with end stage organ failure [1]. Despite outstanding short term graft and patient survival rates, solid organ transplantation continues to face several major challenges including a severe shortage of donor grafts, poor long term graft survival resulting from chronic vascular rejection and major side effects from the need for long term immunosuppressive therapy required for the prevention of rejection [2,3]. The introduction of calcineurin inhibitors (CNI) in the 1980s substantially reduced the incidence and severity of acute graft rejection and improved rates of early engraftment [4]. Although a number of new immunosuppressive agents have been introduced over the past twenty years, this has not markedly affected patient and graft outcomes. In more recent years, immunosuppressive strategies have evolved to reduce long term toxicity and improve graft function, at least in the first few years posttransplant [5,6]. Despite these improvements, patients still depend on the use of non-specific immunosuppression, with it risk of complications, including life-threatening infections, accelerated cardiovascular disease, diabetes and cancer. Moreover, late graft loss, due in large part to chronic rejection, remains an intractable problem. Recognition of the pathogenic role of donor specific antibodies especially in renal, heart and lung transplant recipients has prompted the development of strategies to target B cells, plasma cells and other components of the humoral immune system. The importance of co-stimulatory pathways to allo-recognition and rejection has led to the development of the immunosuppressive agent belatacept to block T cell co-stimulation through CD28 [7,8]. Belatacept has recently been approved by the FDA for recipients of kidney transplants and its use may allow for CNI free immunosuppression with the hope of reduced long term renal and cardiovascular toxicity with no increase in the incidence of allograft rejection. Induction of tolerance in transplant patients would allow for elimination/avoidance of toxic immunosuppressive agents. Strategies that have shown the potential for tolerance in animal models, but not yet in non-human primates or humans, include the combination of co-stimulatory blockade and T cell depletion as well as expansion of antigen specific Treg. Tolerance has been achieved in some HLA mismatched kidney allograft recipients following induction of transient mixed chimerism using donor bone marrow transplantation and a non myeloablative conditioning regimen [9,10]. Technical advances in flow cytometry, antigen specific lymphocyte assays and genome wide analysis have led to the development of powerful immune-monitoring techniques to characterize allo immune responses. It is hoped that these 1044-5323/$ – see front matter © 2011 Published by Elsevier Ltd. doi:10.1016/j.smim.2011.08.013
may eventually allow elimination of dependence on histologic examination of grafts (biopsies) for detection of rejection [11]. Furthermore, molecular or cell based biomarkers are emerging which may be useful to monitor the immune status of the patient. It is hoped that these will detect rejection or immune events before the transplanted organ is damaged. Additionally, patterns of genomic biomarkers are emerging which may predict patients who have achieved tolerance. The ultimate goal of these studies is to identify markers with sufficient predictive value to allow for successful discontinuation of immunotherapy. In this volume of Seminars in Immunology, we have invited experts in basic immunology and transplantation to discuss advances which might be highly relevant to advancing solid organ transplantation. In most instances we invited experts from two different institutions to discuss advances in their respective fields, focusing on controversies, so that differencing perspectives could be synthesized for the reader. Dr F. Lakkis discusses how the innate immune system recognizes non-microbial non-self such as transplant antigens. He describes the principal mechanisms of non-self or damaged self recognition by the innate immune system, including the role of pattern recognition receptors and the danger hypothesis. Wekerle and Sayegh provide an update on the effects of disrupting T cell costimulation on the allo response. They discuss the positive signals involved in T cell activation and described how negative signals inhibit T cell activation and promote tolerance. They discuss the evolution of these concepts for development of co-stimulatory pathways as therapeutic targets for organ transplantation. It is now appreciated that the humoral immune system is a significant barrier to solid organ transplantation due to antibody-mediated recognition of non-self proteins and carbohydrates expressed on transplanted organs. Although the presence of these antibodies was previously considered to be a contraindication to transplantation, Montogomery and colleagues provide data on new ways of testing for these antibodies and on therapeutic strategies that have now made it possible to successfully cross certain antibody barriers. The ability of dendritic cells (DC) to regulate both innate and adaptive immune responses suggests an approach to directing alloimmune responses towards transplant tolerance and away from rejection. Angus Thomson and colleagues provide important new information on the use of DC in tolerogenic strategies in clinical transplantation, including source, isolation and purification techniques, route and timing of administration and combination with immunosuppressive therapy. Many types of regulatory T cells are thought to maintain selftolerance and control of immune responses to foreign antigens. In the article by Shalev et al. the major regulatory T cell subsets
Editorial / Seminars in Immunology 23 (2011) 222–223
described over the past decade and their role in transplantation are discussed with special emphasis on CD4+ CD25+ FoxP3+ regulatory T cells. They discuss proposed mechanisms for their suppressive activity, including generation of inhibitory cytokines, induced death or perturbation of effector cells mediated by changes in extracellular nucleotide/nucleoside fluxes with alterations in intracellular signaling molecules, including cyclic AMP, and inhibition of DC function. Levings and Wood review mechanisms in which Treg could be manipulated or expanded in vivo and the potential of in vitro expanded/generated Treg for cellular therapy. Strober et al. define how novel allogeneic hematopoietic cell transplantation (HCT) approaches have been used to treat hematologic mechanisms and the potential of these reduced toxicity regimens to be useful for organ allograft tolerance induction. They review two successful approaches to HCT that involved reduced intensity conditioning regimens that were associated with improvements in safety in patients with hematologic malignancies, even in the challenging setting of full HLA haplotype mismatch. They discuss how these strategies have been successfully applied for induction of organ allograft tolerance in humans. Advances in gene profiling, sequencing, proteomics and bioinformatics now herald the potential for personalized monitoring and therapeutics in the field of transplantation, with the hope of improving graft survival and reducing patient morbidity from overimmunosuppression. In their article, Salomon and Sarwal summarize the current status of potentially useful technologies available for genomics and proteomics in transplantation, defining the challenges facing their clinical application. Successful adoption of these technologies would usher in a new age of patient care by replacing non specific, invasive techniques with noninvasive, effective and specific tests for patients undergoing solid organ transplantation. We believe that the major advances in our understanding of the immunology of rejection and development of tolerance offers the hope that in the very near future patients will be treated post-transplant with personalized approaches to immunosuppression. Furthermore, we also believe that tolerance will ultimately be achievable in many transplant patients, allowing transplantation without the need for long-term immunosuppression.
223
References [1] Levy GA. Progress in transplantation. Therapeutic Drug Monitoring 2010;32:246–9. [2] Sayegh MH, Carpenter CB. Transplantation 50 years later—progress, challenges, and promises. The New England Journal of Medicine 2004;351:2761–6. [3] Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. The New England Journal of Medicine 2002;346:580–90. [4] Hong JC, Kahan BD. Immunosuppressive agents in organ transplantation: past, present, and future. Seminars in Nephrology 2000;20:108–25. [5] Selzner N, Grant DR, Shalev I, Levy GA. The immunosuppressive pipeline: meeting unmet needs in liver transplantation. Liver Transplantation: Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2010;16:1359–72. [6] Vincenti F. What’s in the pipeline? New immunosuppressive drugs in transplantation. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2002;2:898–903. [7] Larsen CP, Grinyo J, Medina-Pestana J, Vanrenterghem Y, Vincenti F, Breshahan B, et al. Belatacept-based regimens versus a cyclosporine A-based regimen in kidney transplant recipients: 2-year results from the BENEFIT and BENEFIT-EXT studies. Transplantation 2010;90:1528–35. [8] Wojciechowski D, Vincenti F. How the development of new biological agents may help minimize immunosuppression in kidney transplantation: the impact of belatacept. Current Opinion in Organ Transplantation 2010 [epub ahead of print]. [9] Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. The New England Journal of Medicine 2008;358:362–8. [10] Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. The New England Journal of Medicine 2008;358:353–61. [11] Naesens M, Sarwal MM. Molecular diagnostics in transplantation. Nature Reviews Nephrology 2010;6:614–28.
Megan Sykes Columbia Center for Translational Immunology, Columbia University Medical Center, 650 West 168th Street, BB 1512, New York, NY, United States Gary Levy ∗ University of Toronto Transplant Institute, Toronto General Hospital, NCSB 11-1236, 585 University Avenue, Toronto, Ontario, Canada M5G 2N2 ∗ Corresponding author. E-mail addresses: [email protected] (M. Sykes), [email protected] (G. Levy)