Transplantation Tolerance
Transplantation Tolerance
What's the latest in approaches to transplantation tolerance? Find out in this easy-to-navigate collection of recent MEDLINE Abstracts compiled by the editors at Medscape Transplantation.
Sachs DH
Clin Immunol. 2000;95(1 Pt 2):S63-S68
The induction of tolerance to transplanted organs could make transplantation safer and more uniformly successful. One of the most promising approaches currently being investigated involves the induction of deletional tolerance through the establishment of "mixed chimerism." In this laboratory, we first studied mixed chimerism as an approach to transplantation tolerance in mice, using a nonmyeloablative preparative regimen consisting of 300 R whole-body irradiation, 700 R thymic irradiation, and treatment with monoclonal antibodies to CD4 and CD8. This approach has subsequently been extended successfully to the induction of tolerance to renal transplants in fully mismatched cynomolgus monkeys. In addition, the same approach, with minor modifications, has been found effective in producing mixed chimerism and transplantation tolerance in the concordant xenogeneic baboon to cynomolgus monkey species combination. Because pigs have many advantages as a potential xenograft donor for humans, we are also trying to extend our nonmyeloablative regimen for production of mixed chimerism to the discordant pig-primate combination. We have used absorption of natural antibodies to prevent hyperacute rejection and then proceeded with a mixed chimerism approach. Administration of pig hematopoietic stem cells along with pig recombinant cytokines (SCF and IL-3) to primates has enabled the pig bone marrow to survive in these xenogeneic hosts for over 6 months. This chimerism has apparently been sufficient to markedly diminish T cell immunity and the induction of new T-cell-dependent responses. However, to date we have not succeeded in preventing the return of natural antibodies, which appear to be the cause of eventual loss of organ transplants and are the subject of further intensive investigations.
Gudmundsdottir H, Turka LA
Semin Nephrol. 2000;20:209-216
The goal of transplantation is to induce tolerance to the transplanted tissue. We believe that this will only be possible by exploring strategies normally used to endure and maintain self-tolerance. Tolerance can be defined as a state where the immune system does not respond to a specific antigen. This is in sharp contrast with immunosuppression, which decreases the immune response to a myriad of antigens and requires continued medication. T cells play an essential role in the immune response to alloantigens, because animals devoid of T cells do not reject transplanted organs. In this article we will focus on the mechanism of T cell tolerance and how the immune system may be manipulated to achieve tolerance to alloantigens.
Wekerle T, Kurtz J, Ito H, et al
Nat Med. 2000;6:464-469
Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.
Staerz UD, Lee DS, Qi Y
Immunol Today. 2000;2:172-176
The veto effect has been shown to inhibit T cells efficiently and specifically. However, since CD8+ T cells are used as the tolerizing veto cells, this strategy cannot provide complete tolerance to a transplanted organ nor remove pathogenic T cells of an autoimmune disease. Here Uwe Staerz and colleagues review hybrid antibody-mediated inhibition of T cells that exploits the effectiveness and specificity of veto, yet broadens its reach to tissue-specific T cells.
Meyer D, Loffeler S, Otto C, et al
Transpl Int. 2000;13:12-20
The predictive value of chimerism was evaluated in three different transplantation models in the rat without immunosuppression: small bowel- (SBTx), liver- (LTx), and liver/small bowel transplantation (LSBTx) were performed in the Brown Norway (BN)-to-Lewis-(LEW) strain combination. Immunohistochemistry and flow cytometry were used to identify donor cells in the recipient's spleen. Their number did not change significantly during transient rejection or tolerance after LTx and LSBTx. However, the amount of donor-derived nonparenchymal cells within the liver allograft including antigen-presenting cells (APCs), such as dendritic and Kupffer cells, clearly mirrored the recipient's immune status: as expected, their number decreased during rejection, but recovered considerably during and after tolerance induction. We conclude that donor cells in the periphery of the recipient correlate with the presence of the allograft, but do not seem to influence graft acceptance actively. However, the kinetics of the detected donor APC population in the liver suggests their important role in modifying the recipient's immune response towards tolerance.
Helderman JH, Goral S
Semin Nephrol. 2000;20:83-86
Despite tremendous advances in organ transplantation over the past 40 years, life-long immunosuppression is still required to maintain the transplanted organ. The induction of human tolerance to defined foreign antigens while maintaining completely intact all the rest of the immune repertoire, in the absence of maintenance immunosuppression, continues to be the dream of the transplant scientist and clinician, the "Holy Grail," the quest which energizes much recent research. This article presents an overview on recent developments on transplantation tolerance.
Calne R, Moffatt SD, Friend PJ, et al.
Nippon Geka Gakkai Zasshi. 2000;101:301-306
The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.
O'Connell PJ, Burlingham WJ
J Leukoc Biol. 1999;66:301-305
Donor-derived leukocytes are known to persist in the peripheral blood of organ allograft recipients after withdrawal of all immunosuppressive drug therapy and can exert a donor-specific veto effect. Antigen-presenting cells (APC), in particular dendritic cells (DC), have been proposed as a candidate for this veto leukocyte. Myeloid DC were derived from the peripheral blood of two ion-compliant organ transplant recipients: D. S., a heart transplant recipient, and J. M., a liver transplant recipient. Donor-specific signal was enriched in the cultured DC fraction relative to whole blood for both patients. The clinical outcome in each patient was different: D. S. lost his heart allograft due to biopsy-proven acute and chronic rejection 2.5 years after discontinuing anti-rejection medication; J. M. continues to maintain adequate liver function. The results have important implications for the planned withdrawal of immunosuppression in tolerance protocols as DC may play a role either in the maintenance of tolerance or immune activation.
Gammie JS, Pham SM
Curr Opin Cardiol. 1999;14:126-132
Mixed bone marrow chimerism (mixed chimerism) is defined by the coexistence of two genetically different bone marrow stem cells in an individual. The chimeric immune system recognizes donor antigen as self, yet is capable of mounting a normal response to third-party antigens. In animal models, mixed chimerism confers donor-specific tolerance for solid-organ and cellular grafts: tissue from the bone marrow donor is permanently accepted by mixed chimeras in the absence of conventional immunosuppressive agents. Clinical application of mixed chimerism to induce transplantation tolerance requires novel approaches to safely and reliably achieve engraftment of donor bone marrow in transplant recipients. Recent advances offer potential solutions to these obstacles and suggest that the application of mixed chimerism to induce tolerance to transplanted organs may soon be a clinical reality.
Exner BG, Acholonu IN, Bergheim M, et al
Acta Haematol. 1999;101:78-81
Transplantation of solid organs and cellular grafts has become clinical routine in the last 30 years. However, the requirement for life-long immunosuppression is associated with infections, malignancies and end-organ toxicity. Moreover, the treatment fails to prevent chronic rejection. The induction of donor-specific transplantation tolerance would solve these problems, but has remained an elusive goal. One approach to achieve transplantation tolerance is through hematopoietic chimerism. This review outlines different concepts of hematopoietic chimerism focusing on macrochimerism. Mixed allogeneic chimerism, also known as macrochimerism, is defined as engraftment of hematopoietic stem cells achieved by bone marrow transplantation (BMT). It discusses the advantages and limitations of the BMT as well as approaches to overcome these limitations in the future.
Dong VM, Womer KL, Sayegh MH
Pediatr Transplant. 1999;3:181-192
Recent advances have enabled researchers to induce tolerance in animal transplant models. Although it has been relatively easy to do so in rodents' it has been much more difficult to translate such strategies into primates. Understanding the cellular and molecular mechanisms of the alloimmune response has prompted the development of novel strategies that may obviate the need for immunosuppression in humans. Mechanisms of tolerance and promising new therapies' as well as the inherent difficulties in bringing them into clinical practice' are reviewed.
Fung JJ
Liver Transpl Surg. 1999; 5(4 Suppl 1):S90-S97
Define the various concepts of transplantation tolerance: Immunologically: unresponsiveness to donor antigens Clinically: ability to discontinue nonspecific immunosuppression Outcome-based: ability to prevent long-term immunologically mediated graft loss (i.e.' chronic rejection). *Understand the various possible mechanism(s) involved in developing transplantation tolerance: Central tolerance: clonal deletion Peripheral tolerance: Blocking antibodies Cytokine imbalance Clonal T-cell anergy Active regulation of T- and B-cell proliferation. *Methods to achieve transplantation tolerance: Macrochimerism: recipient cytoablation and donor reconstitution Microchimerism: bone marrow augmentation' growth factors Intrathymic inoculation: central tolerance? T-cell costimulatory blockade: induction of T-cell anergy. *Limitations of achieving transplantation tolerance: No markers to define tolerance Poor understanding of acute and chronic rejection mechanisms (e.g.' direct v indirect antigen presentation' high- v low-affinity T cells for alloantigen) What cells are involved in the development of tolerance? How stable is clinical tolerance: are the dynamics influenced by nontransplant factors (e.g.' antigenic stimulation by viral factors)? Need for a two-pronged approach: nonspecific phase followed by specific phase?
Hancock WW
Curr Opin Nephrol Hypertens. 1999;8:317-324
Recent advances in transplant immunology are wide ranging. These include the testing of new approaches to tolerance induction by the interruption of co-stimulatory pathways, the analysis of molecular events underlying the development of chronic rejection, efforts to increase the donor pool by consideration of the role of brain death in donor-dependent outcomes of allografting, and progress towards renal xenografting. In addition, current molecular approaches are paramount to understanding key events from ischemia/reperfusion injury and the role of apoptosis in remodelling of the host immune response to an allograft. Important papers relevant to the field from the past year are reviewed with an eye to clinically relevant new data involving renal transplantation.
Wells AD, Li XC, Li Y, et al
Nat Med. 1999;5:1303-1307
The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.
Onodera K, Chandraker A, Volk HD, et al
Transplantation. 1999;68:288-293
Background: CD4-targeted therapy or blocking of CD28-B7 T-cell costimulation may produce indefinite cardiac allograft survival in presensitized rats. This study analyzes the immune events associated with tolerance pathways after the blockade of activation signal 1 (CD4 monoclonal antibody [mAb]) or signal 2 (CTLA4Ig).
Methods and Results: Lewis rats sensitized with Brown Norway skin grafts reject LBNF1 cardiac allografts in <36 hr. Animals were treated with RIB-5/2, a nondepleting CD4 mAb, or with CTLA4Ig + LBNF1 spleen cells. RIB-5/2 monotherapy uniformly produced permanent cardiac graft acceptance, whereas CTLA4Ig produced indefinite graft survival in about 50% of sensitized rats. Spleen cells (100 x 10(6)) from CD4 mAb-treated rats conferred donor-specific tolerance after transfer into new sets of recipients. This tolerant state could be then transferred with regulatory cells in an infectious manner into new cohorts of engrafted rats. In contrast, features of infectious tolerance could be detected in CTLA4Ig-treated hosts after infusion of >300 x 10(6) of splenocytes. CD4 mAb therapy abolished the transcription of both T helper (Th)1 and Th2 cytokines compared with rejecting controls. In contrast, CTLA4Ig treatment resulted in a selective sparing of Th2-type cytokines. Surviving grafts in both groups were largely protected from signs of chronic rejection.
Conclusions: CD4 mAb-induced blockage of activation signal 1 or CTLA4Ig-mediated blockage of costimulatory signal 2 may induce a true transplantation tolerance in sensitized rats, as documented by permanent graft acceptance and attenuation of chronic injury. The infectious pathway operates in a cell dose-dependent manner. Th2-type deviation in the graft itself is not required for tolerance maintenance, and it does not necessarily lead to chronic injury.
Zhai Y, Kupiec-Weglinski JW
Curr Opin Immunol. 1999;11:497-503
There has been considerable recent progress in the characterization of the regulatory T cells that mediate tolerance in a number of transplantation models. The conditions that facilitate the generation of regulatory T cells point to the thymus, the nature of immune suppression and the dose of immunosuppressive agent(s) being important. Putative mechanisms of immune regulation by regulatory T cells, particularly in the 'infectious' tolerance pathway, include Th2-type cytokines (IL-4, IL-10 and transforming growth factor beta) that may play a direct role as an indispensable requirement or may contribute indirectly as a favorable milieu for acquisition of tolerance. Anergic T cells may suppress immune responses via either cytokine competition or antigen-presenting cells. Models of autoimmune disease, in which regulatory T cells were shown to represent a distinct thymus-derived T cell subset, also suggest the role of antigen-presenting cells in mediating immune suppression. Progress has also been made in generating and characterizing regulatory T cells in vitro.
Turvey SE, Wood KJ
Int Surg. 1999;84:279-290
The field of organ transplantation is entering a very exciting phase in which tolerance induction may become a therapeutic possibility. The induction of tolerance would allow patients to enjoy the benefits of their transplanted organ without risking the mortality and morbidity associated with long-term pharmacological immunosuppression. In this review, we explore the immunobiology of solid organ transplantation, discussing the immunological mechanisms responsible for allograft rejection, and outlining the rational behind a range of successful experimental tolerance induction strategies.
Kirk AD
Crit Rev Immunol. 1999;19:349-388
Ever since the beginning of clinical transplantation, investigators have searched for a way to transplant tissues from one person to another without chronic immunosuppression. That goal, known as allograft tolerance, has remained clinically elusive. In the past decade, however, many of the fundamental principles of tolerance have been redefined, and biological agents capable of exploiting them in vivo have been developed. Accordingly, experimental methods for tolerance induction have rapidly evolved in concert with a growing understanding of physiological tolerance to self and the development of novel immunoreactive reagents. In general, old world monkeys have become the pre-clinical testing ground for methods that have shown reasonable promise for clinical application, particularly antibodies or other biological agents with limited cross-species reactivity. As such, a survey of the nonhuman primate experience in transplantation is representative of all reasonably successful experimental attempts to develop clinically applicable tolerance regimens. This article summarizes many of the concepts currently unfolding in the tolerance literature. It also reviews the techniques for tolerance induction that have been and are currently being investigated in nonhuman primates. The validity of these models is summarized, and the older literature is reinterpreted in light of recent changes in our understanding of tolerance.
Waldmann H
Nat Med. 1999;5:1245-1248
Our understanding of tolerance mechanisms has progressed to the point that tolerance-induction protocols are being tested in humans for organ transplantation. However, a range of scientific, ethical, logistic and commercial issues have arisen, and must be resolved before tolerance induction for human allograft patients can become a reality.
What's the latest in approaches to transplantation tolerance? Find out in this easy-to-navigate collection of recent MEDLINE Abstracts compiled by the editors at Medscape Transplantation.
Sachs DH
Clin Immunol. 2000;95(1 Pt 2):S63-S68
The induction of tolerance to transplanted organs could make transplantation safer and more uniformly successful. One of the most promising approaches currently being investigated involves the induction of deletional tolerance through the establishment of "mixed chimerism." In this laboratory, we first studied mixed chimerism as an approach to transplantation tolerance in mice, using a nonmyeloablative preparative regimen consisting of 300 R whole-body irradiation, 700 R thymic irradiation, and treatment with monoclonal antibodies to CD4 and CD8. This approach has subsequently been extended successfully to the induction of tolerance to renal transplants in fully mismatched cynomolgus monkeys. In addition, the same approach, with minor modifications, has been found effective in producing mixed chimerism and transplantation tolerance in the concordant xenogeneic baboon to cynomolgus monkey species combination. Because pigs have many advantages as a potential xenograft donor for humans, we are also trying to extend our nonmyeloablative regimen for production of mixed chimerism to the discordant pig-primate combination. We have used absorption of natural antibodies to prevent hyperacute rejection and then proceeded with a mixed chimerism approach. Administration of pig hematopoietic stem cells along with pig recombinant cytokines (SCF and IL-3) to primates has enabled the pig bone marrow to survive in these xenogeneic hosts for over 6 months. This chimerism has apparently been sufficient to markedly diminish T cell immunity and the induction of new T-cell-dependent responses. However, to date we have not succeeded in preventing the return of natural antibodies, which appear to be the cause of eventual loss of organ transplants and are the subject of further intensive investigations.
Gudmundsdottir H, Turka LA
Semin Nephrol. 2000;20:209-216
The goal of transplantation is to induce tolerance to the transplanted tissue. We believe that this will only be possible by exploring strategies normally used to endure and maintain self-tolerance. Tolerance can be defined as a state where the immune system does not respond to a specific antigen. This is in sharp contrast with immunosuppression, which decreases the immune response to a myriad of antigens and requires continued medication. T cells play an essential role in the immune response to alloantigens, because animals devoid of T cells do not reject transplanted organs. In this article we will focus on the mechanism of T cell tolerance and how the immune system may be manipulated to achieve tolerance to alloantigens.
Wekerle T, Kurtz J, Ito H, et al
Nat Med. 2000;6:464-469
Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.
Staerz UD, Lee DS, Qi Y
Immunol Today. 2000;2:172-176
The veto effect has been shown to inhibit T cells efficiently and specifically. However, since CD8+ T cells are used as the tolerizing veto cells, this strategy cannot provide complete tolerance to a transplanted organ nor remove pathogenic T cells of an autoimmune disease. Here Uwe Staerz and colleagues review hybrid antibody-mediated inhibition of T cells that exploits the effectiveness and specificity of veto, yet broadens its reach to tissue-specific T cells.
Meyer D, Loffeler S, Otto C, et al
Transpl Int. 2000;13:12-20
The predictive value of chimerism was evaluated in three different transplantation models in the rat without immunosuppression: small bowel- (SBTx), liver- (LTx), and liver/small bowel transplantation (LSBTx) were performed in the Brown Norway (BN)-to-Lewis-(LEW) strain combination. Immunohistochemistry and flow cytometry were used to identify donor cells in the recipient's spleen. Their number did not change significantly during transient rejection or tolerance after LTx and LSBTx. However, the amount of donor-derived nonparenchymal cells within the liver allograft including antigen-presenting cells (APCs), such as dendritic and Kupffer cells, clearly mirrored the recipient's immune status: as expected, their number decreased during rejection, but recovered considerably during and after tolerance induction. We conclude that donor cells in the periphery of the recipient correlate with the presence of the allograft, but do not seem to influence graft acceptance actively. However, the kinetics of the detected donor APC population in the liver suggests their important role in modifying the recipient's immune response towards tolerance.
Helderman JH, Goral S
Semin Nephrol. 2000;20:83-86
Despite tremendous advances in organ transplantation over the past 40 years, life-long immunosuppression is still required to maintain the transplanted organ. The induction of human tolerance to defined foreign antigens while maintaining completely intact all the rest of the immune repertoire, in the absence of maintenance immunosuppression, continues to be the dream of the transplant scientist and clinician, the "Holy Grail," the quest which energizes much recent research. This article presents an overview on recent developments on transplantation tolerance.
Calne R, Moffatt SD, Friend PJ, et al.
Nippon Geka Gakkai Zasshi. 2000;101:301-306
The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.
O'Connell PJ, Burlingham WJ
J Leukoc Biol. 1999;66:301-305
Donor-derived leukocytes are known to persist in the peripheral blood of organ allograft recipients after withdrawal of all immunosuppressive drug therapy and can exert a donor-specific veto effect. Antigen-presenting cells (APC), in particular dendritic cells (DC), have been proposed as a candidate for this veto leukocyte. Myeloid DC were derived from the peripheral blood of two ion-compliant organ transplant recipients: D. S., a heart transplant recipient, and J. M., a liver transplant recipient. Donor-specific signal was enriched in the cultured DC fraction relative to whole blood for both patients. The clinical outcome in each patient was different: D. S. lost his heart allograft due to biopsy-proven acute and chronic rejection 2.5 years after discontinuing anti-rejection medication; J. M. continues to maintain adequate liver function. The results have important implications for the planned withdrawal of immunosuppression in tolerance protocols as DC may play a role either in the maintenance of tolerance or immune activation.
Gammie JS, Pham SM
Curr Opin Cardiol. 1999;14:126-132
Mixed bone marrow chimerism (mixed chimerism) is defined by the coexistence of two genetically different bone marrow stem cells in an individual. The chimeric immune system recognizes donor antigen as self, yet is capable of mounting a normal response to third-party antigens. In animal models, mixed chimerism confers donor-specific tolerance for solid-organ and cellular grafts: tissue from the bone marrow donor is permanently accepted by mixed chimeras in the absence of conventional immunosuppressive agents. Clinical application of mixed chimerism to induce transplantation tolerance requires novel approaches to safely and reliably achieve engraftment of donor bone marrow in transplant recipients. Recent advances offer potential solutions to these obstacles and suggest that the application of mixed chimerism to induce tolerance to transplanted organs may soon be a clinical reality.
Exner BG, Acholonu IN, Bergheim M, et al
Acta Haematol. 1999;101:78-81
Transplantation of solid organs and cellular grafts has become clinical routine in the last 30 years. However, the requirement for life-long immunosuppression is associated with infections, malignancies and end-organ toxicity. Moreover, the treatment fails to prevent chronic rejection. The induction of donor-specific transplantation tolerance would solve these problems, but has remained an elusive goal. One approach to achieve transplantation tolerance is through hematopoietic chimerism. This review outlines different concepts of hematopoietic chimerism focusing on macrochimerism. Mixed allogeneic chimerism, also known as macrochimerism, is defined as engraftment of hematopoietic stem cells achieved by bone marrow transplantation (BMT). It discusses the advantages and limitations of the BMT as well as approaches to overcome these limitations in the future.
Dong VM, Womer KL, Sayegh MH
Pediatr Transplant. 1999;3:181-192
Recent advances have enabled researchers to induce tolerance in animal transplant models. Although it has been relatively easy to do so in rodents' it has been much more difficult to translate such strategies into primates. Understanding the cellular and molecular mechanisms of the alloimmune response has prompted the development of novel strategies that may obviate the need for immunosuppression in humans. Mechanisms of tolerance and promising new therapies' as well as the inherent difficulties in bringing them into clinical practice' are reviewed.
Fung JJ
Liver Transpl Surg. 1999; 5(4 Suppl 1):S90-S97
Define the various concepts of transplantation tolerance: Immunologically: unresponsiveness to donor antigens Clinically: ability to discontinue nonspecific immunosuppression Outcome-based: ability to prevent long-term immunologically mediated graft loss (i.e.' chronic rejection). *Understand the various possible mechanism(s) involved in developing transplantation tolerance: Central tolerance: clonal deletion Peripheral tolerance: Blocking antibodies Cytokine imbalance Clonal T-cell anergy Active regulation of T- and B-cell proliferation. *Methods to achieve transplantation tolerance: Macrochimerism: recipient cytoablation and donor reconstitution Microchimerism: bone marrow augmentation' growth factors Intrathymic inoculation: central tolerance? T-cell costimulatory blockade: induction of T-cell anergy. *Limitations of achieving transplantation tolerance: No markers to define tolerance Poor understanding of acute and chronic rejection mechanisms (e.g.' direct v indirect antigen presentation' high- v low-affinity T cells for alloantigen) What cells are involved in the development of tolerance? How stable is clinical tolerance: are the dynamics influenced by nontransplant factors (e.g.' antigenic stimulation by viral factors)? Need for a two-pronged approach: nonspecific phase followed by specific phase?
Hancock WW
Curr Opin Nephrol Hypertens. 1999;8:317-324
Recent advances in transplant immunology are wide ranging. These include the testing of new approaches to tolerance induction by the interruption of co-stimulatory pathways, the analysis of molecular events underlying the development of chronic rejection, efforts to increase the donor pool by consideration of the role of brain death in donor-dependent outcomes of allografting, and progress towards renal xenografting. In addition, current molecular approaches are paramount to understanding key events from ischemia/reperfusion injury and the role of apoptosis in remodelling of the host immune response to an allograft. Important papers relevant to the field from the past year are reviewed with an eye to clinically relevant new data involving renal transplantation.
Wells AD, Li XC, Li Y, et al
Nat Med. 1999;5:1303-1307
The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.
Onodera K, Chandraker A, Volk HD, et al
Transplantation. 1999;68:288-293
Background: CD4-targeted therapy or blocking of CD28-B7 T-cell costimulation may produce indefinite cardiac allograft survival in presensitized rats. This study analyzes the immune events associated with tolerance pathways after the blockade of activation signal 1 (CD4 monoclonal antibody [mAb]) or signal 2 (CTLA4Ig).
Methods and Results: Lewis rats sensitized with Brown Norway skin grafts reject LBNF1 cardiac allografts in <36 hr. Animals were treated with RIB-5/2, a nondepleting CD4 mAb, or with CTLA4Ig + LBNF1 spleen cells. RIB-5/2 monotherapy uniformly produced permanent cardiac graft acceptance, whereas CTLA4Ig produced indefinite graft survival in about 50% of sensitized rats. Spleen cells (100 x 10(6)) from CD4 mAb-treated rats conferred donor-specific tolerance after transfer into new sets of recipients. This tolerant state could be then transferred with regulatory cells in an infectious manner into new cohorts of engrafted rats. In contrast, features of infectious tolerance could be detected in CTLA4Ig-treated hosts after infusion of >300 x 10(6) of splenocytes. CD4 mAb therapy abolished the transcription of both T helper (Th)1 and Th2 cytokines compared with rejecting controls. In contrast, CTLA4Ig treatment resulted in a selective sparing of Th2-type cytokines. Surviving grafts in both groups were largely protected from signs of chronic rejection.
Conclusions: CD4 mAb-induced blockage of activation signal 1 or CTLA4Ig-mediated blockage of costimulatory signal 2 may induce a true transplantation tolerance in sensitized rats, as documented by permanent graft acceptance and attenuation of chronic injury. The infectious pathway operates in a cell dose-dependent manner. Th2-type deviation in the graft itself is not required for tolerance maintenance, and it does not necessarily lead to chronic injury.
Zhai Y, Kupiec-Weglinski JW
Curr Opin Immunol. 1999;11:497-503
There has been considerable recent progress in the characterization of the regulatory T cells that mediate tolerance in a number of transplantation models. The conditions that facilitate the generation of regulatory T cells point to the thymus, the nature of immune suppression and the dose of immunosuppressive agent(s) being important. Putative mechanisms of immune regulation by regulatory T cells, particularly in the 'infectious' tolerance pathway, include Th2-type cytokines (IL-4, IL-10 and transforming growth factor beta) that may play a direct role as an indispensable requirement or may contribute indirectly as a favorable milieu for acquisition of tolerance. Anergic T cells may suppress immune responses via either cytokine competition or antigen-presenting cells. Models of autoimmune disease, in which regulatory T cells were shown to represent a distinct thymus-derived T cell subset, also suggest the role of antigen-presenting cells in mediating immune suppression. Progress has also been made in generating and characterizing regulatory T cells in vitro.
Turvey SE, Wood KJ
Int Surg. 1999;84:279-290
The field of organ transplantation is entering a very exciting phase in which tolerance induction may become a therapeutic possibility. The induction of tolerance would allow patients to enjoy the benefits of their transplanted organ without risking the mortality and morbidity associated with long-term pharmacological immunosuppression. In this review, we explore the immunobiology of solid organ transplantation, discussing the immunological mechanisms responsible for allograft rejection, and outlining the rational behind a range of successful experimental tolerance induction strategies.
Kirk AD
Crit Rev Immunol. 1999;19:349-388
Ever since the beginning of clinical transplantation, investigators have searched for a way to transplant tissues from one person to another without chronic immunosuppression. That goal, known as allograft tolerance, has remained clinically elusive. In the past decade, however, many of the fundamental principles of tolerance have been redefined, and biological agents capable of exploiting them in vivo have been developed. Accordingly, experimental methods for tolerance induction have rapidly evolved in concert with a growing understanding of physiological tolerance to self and the development of novel immunoreactive reagents. In general, old world monkeys have become the pre-clinical testing ground for methods that have shown reasonable promise for clinical application, particularly antibodies or other biological agents with limited cross-species reactivity. As such, a survey of the nonhuman primate experience in transplantation is representative of all reasonably successful experimental attempts to develop clinically applicable tolerance regimens. This article summarizes many of the concepts currently unfolding in the tolerance literature. It also reviews the techniques for tolerance induction that have been and are currently being investigated in nonhuman primates. The validity of these models is summarized, and the older literature is reinterpreted in light of recent changes in our understanding of tolerance.
Waldmann H
Nat Med. 1999;5:1245-1248
Our understanding of tolerance mechanisms has progressed to the point that tolerance-induction protocols are being tested in humans for organ transplantation. However, a range of scientific, ethical, logistic and commercial issues have arisen, and must be resolved before tolerance induction for human allograft patients can become a reality.
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