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The future of new immunosuppressive drugs
The Future of New Immunosuppressive Drugs L.C. Paul
C
LINICALLY, immunosuppression is defined as the inhibition of a rate-limiting step in the immune response while avoiding the complications of immunodeficiency.1 The immunosuppressive drugs currently in use effectively inhibit T-lymphocyte– dependent immune responses but are relatively ineffective in preventing or treating chronic rejection. Moreover, most drugs have compound-specific toxicities that impair patient and graft survival.2,3 Therefore, there is a need to develop drugs that selectively inhibit acute and chronic rejection, allow the emergence of transplantation tolerance, while leaving the immune response to other antigens intact. Transplantation tolerance is defined as the loss of immunocompetence of lymphocytes to specific alloantigens without the continued need to administer immunosuppressive agents. Transplantation tolerance is well documented in animal models but has been difficult to establish clinically because of the lack of appropriate in vitro tests. REJECTION OR TOLERANCE
Rejection and tolerance are active immunologic processes that require exposure of recipient T-lymphocytes to donor antigens. After engagement of the T-cell receptor (TCR) with antigen, the lymphocyte has a menu of possible responses including full activation, partial activation, apoptosis, anergy, or neglect. The fate of the T-cell depends on the context in which the antigenic encounter occurs. Experimental studies have suggested that bone marrowderived antigen-presenting cells (APCs) existing in the graft at the time of transplantation are responsible for the induction of primary acute rejection. Experiments in the late 1970s have shown that F1 rat kidney allografts transplanted into a parental strain recipient under the cover of a short course of immunosuppression are not rejected when immunosuppression is withdrawn. When these allografts were retransplanted into a second parental strain, they were accepted in the absence of any immunosuppression.4 In contrast, if the retransplanted grafts were reconstituted with donor strain APCs, they were rejected at the same rate as primary grafts between the same donor and recipient strains.5 However, with time it becomes more difficult to induce acute rejection, even of grafts containing donor APCs, suggesting the emergence of a population of regulatory cells that maintain a state of tolerance.6 Based on these and other experiments, it has been proposed that engagement of recipient T-lymphocytes via their TCR␣/ V 0041-1345/99/$–see front matter PII S0041-1345(99)00787-3 16S
region with major histocompatibility complex (MHC) plus peptide on donor APCs induces an immune response that results in acute rejection, provided that the APCs deliver a second signal through one or more costimulatory molecules and growth-promoting cytokines are produced by the activated T-lymphocytes. Antigen presentation by donor APCs has been designated the direct route and is probably responsible for the early induction of a posttransplant immune response. On the other hand, direct recognition of graft parenchymal cells can induce donor-specific T-cell tolerance as graft parenchymal cells express donor antigens but do not provide costimulation.7 In addition to direct sensitization, there is evidence that donor antigens derived from APCs and parenchymal cells are also presented to the recipient immune system by recipient APC through the so-called indirect sensitization route.8 Donor antigens presented through the indirect route are taken up and processed by recipient APCs and presented to T-lymphocytes like any other nominal antigen. The indirect allosensitization route is likely to be important in chronic rejection. Defective APC-TCR interactions, lack of costimulation, or APC-TCR interactions in the presence of certain cytokines may result in tolerance.9,10 Furthermore, it has been suggested that tolerance induction depends on the establishment of a state of donor ‘microchimerism’11 which is the persistence of donor type hematopoietic cells in an allogeneic recipient. The precise mechanism by which microchimerism mediates prolonged graft survival is not clear, nor is it known what the relation is between these cells and the cells involved in induction of acute rejection. Great interest has emerged in posttransplant targeting of T-cell costimulatory pathways. Costimulators determine whether engagement of the TCR by MHC products will lead to activation, anergy, apoptosis, or neglect. In most models, blockade of the CD40/CD40L or B7/CD28 pathways separately prevents acute, but not chronic rejection,12,13 whereas simultaneous blockade of both pathways effectively aborts T-cell clonal expansion, promotes long-
From the Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands. Address reprint requests to L.C. Paul, MD, Department of Nephrology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail L.C.Paul@Nephrology. Medfac.LeidenUniv.nl. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31 (Suppl 7A), 16S–17S (1999)
FUTURE OF NEW IMMUNOSUPPRESSIVE DRUGS
term survival of fully allogeneic grafts and inhibits chronic rejection.14,15 Kirk et al13 reported graft survival of ⬎180 days in a small series of Rhesus monkey renal transplants treated with a 28-day course of anti-CD40L monoclonal antibody and the CTLA4Ig fusion protein. Thus, simultaneous blockade of the CD40/CD40L and B7/CD28 pathways offers exciting clinical prospects. Many experimental forms of pretransplant tolerance induction have been proposed clinically. All protocols include pretransplant exposure to donor antigens with or without concomitant immunosuppression. In different models of rat renal16 or cardiac17,18 transplantation, such protocols prevent acute and chronic rejection, but their clinical applicability remains to be established.19
TISSUE CHANGES ASSOCIATED WITH GRAFT ACCEPTANCE
Most efforts to induce graft acceptance in the absence of continuous immunosuppressive medication have mainly focused on manipulation of the recipient immune system, while little attention has been given to the possibility of changing the graft’s resistance to injury. The observation that ABO-incompatible kidney grafts that survive the early posttransplant period continue to function despite the presence of high titers of antibodies against graft antigens led to the introduction of the concept of ‘graft adaptation,’20 the survival of an organ graft in the presence of antigraft antibodies and complement. While the proinflammatory response of, for example, endothelial cells following activation has been described extensively, less information is available regarding induction of tissue protective genes. Following cell activation, a number of genes are upregulated which protect the cell from apoptosis and suppress the proinflammatory response. A20 is a tissue protective gene that inhibits activation of NF-B, a transcription factor that plays a key role in the induction of proinflammatory events.21 Bcl-2 and Bcl-x are antiapoptotic genes, and hemoxygenase-1 (HO-1) prevents oxidant-stressed endothelial induction of adhesion molecules.22 HO-1 can also ameliorate tissue damage through the generation of heme breakdown products such as bilirubin, which exerts anticomplement or antioxidant effects, and carbon monoxide, which has vasodilatory and antiplatelet effects.23 The concept that tissue damage induces resistance to further injury was proposed as early as 1916 as an explanation for the observation that kidneys that recovered from uranium poisoning markedly resisted injury on further exposure. More recently it was shown that induction of the HO-1 gene using ferriprotoporphyrin IX chloride prior to induction of nephrotoxic serum nephritis has a protective effect on kidney function and structure.24 Upregulation of protective genes has been reported in grafts that are protected from hyperacute, acute and chronic rejection.25,26 Therefore, a goal for future immunosuppressive drugs is to induce sets of genes that protect the tissue against injury.
17S
FUTURE IMMUNOSUPPRESSIVE DRUGS
Immunosuppression should be based on an understanding of the immune response. While refining the intracellular target molecules of the various immunosuppressive drugs may create the potential to design agents that exert lymphocyte-selective immunosuppression without compoundspecific adverse events, the ultimate goal remains to be the establishment of donor-specific tolerance. New immunosuppressive drugs should prevent acute and chronic rejection while preserving immune responsiveness to viral, fungal, and tumor antigens. As not all graft inflammation results from immune reactions, future drugs should also inhibit graft recruitment of inflammatory cells that result from stimuli such as ischemia-reperfusion damage. Such treatment regimens should be devoid of intrinsic toxicity, easy to administer, affordable, and have no negative impact on quality of life.27 Finally, as the tissue reaction to damage is determined by its ability to resist injury, graft damage could be attenuated by manipulation of the graft to upregulate tissue protective genes.
REFERENCES 1. Halloran PF: Transplant Proc 28(suppl 1):11, 1996 2. Paul LC: Transplant Proc 30:4001, 1998 3. Sells RA: Transplant Proc 30(suppl 8A):14S, 1998 4. Batchelor JR, Welsh KI, Maynard A, et al: J Exp Med 150:455, 1979 5. Lechler RI, Batchelor JR: J Exp Med 155:31, 1982 6. Hall B, Jelbart K, Gurleyand K, et al: J Exp Med 162:1683, 1985 7. Frasca L, Marelli-Berg F, Imami N, et al: Kidney Int 53:679, 1998 8. Liu Z, Sun Y-K, Xi Y-P, et al: J Exp Med 177:1643, 1993 9. Madrenas J, Germain RN: Semin Immunol 8:83, 1996 10. Waldmann H, Cobbold S: Annu Rev Immunol 16:619, 1998 11. Starzl TE, Demetris AJ, Murase N, et al: Immunol Today 14:326, 1993 12. Larsen CP, Pearson TC: Curr Opin Immunol 9:641, 1997 13. Kirk AD, Harlan DM, Armstrong NN, et al: Proc Natl Acad Sci USA 94:8789, 1997 14. Larsen CP, Elwood ET, Alexander DZ, et al: Nature 381: 434, 1996 15. Subbotin V, Sun H, Chen C, et al: Transplant Proc 30:941, 1998 16. Sayegh MH, Perico N, Gallon L, et al: Transplantation 58:125, 1994 17. Orloff MS, DeMara EM, Coppage ML, et al: Transplantation 59:282, 1995 18. Shin YT, Adams DH, Wyner LR, et al: Transplantation 59:1647, 1995 19. Flye MW, Burton K, Mohanakumar T, et al: Transplantation 60:1395, 1995 20. Alexandre GPJ, Squifflet JP, De Bruyere M, et al: Transplant Proc 19:4538, 1987 21. Bach FH, Hancock WW, Ferran C: Immunol Today 18:483, 1997
18S 22. Bach FH, Ferran C, Soares M, et al: Nature Med 3:944, 1997 23. Willis D, Moore AR, Frederick R, et al: Nature Med 2:87, 1996 24. Mosley K, Wembridge DE, Cattell V, et al: Kidney Int 53:672, 1998
PAUL 25. Hancock WW, Buelow R, Sayegh MH, et al: Nature Med 4:1392, 1998 26. Soares MP, Lin Y, Anrather J, et al: Nature Med 4:1073, 1998 27. Kahan BD: Transplant Proc 30:2493, 1998
C
LINICALLY, immunosuppression is defined as the inhibition of a rate-limiting step in the immune response while avoiding the complications of immunodeficiency.1 The immunosuppressive drugs currently in use effectively inhibit T-lymphocyte– dependent immune responses but are relatively ineffective in preventing or treating chronic rejection. Moreover, most drugs have compound-specific toxicities that impair patient and graft survival.2,3 Therefore, there is a need to develop drugs that selectively inhibit acute and chronic rejection, allow the emergence of transplantation tolerance, while leaving the immune response to other antigens intact. Transplantation tolerance is defined as the loss of immunocompetence of lymphocytes to specific alloantigens without the continued need to administer immunosuppressive agents. Transplantation tolerance is well documented in animal models but has been difficult to establish clinically because of the lack of appropriate in vitro tests. REJECTION OR TOLERANCE
Rejection and tolerance are active immunologic processes that require exposure of recipient T-lymphocytes to donor antigens. After engagement of the T-cell receptor (TCR) with antigen, the lymphocyte has a menu of possible responses including full activation, partial activation, apoptosis, anergy, or neglect. The fate of the T-cell depends on the context in which the antigenic encounter occurs. Experimental studies have suggested that bone marrowderived antigen-presenting cells (APCs) existing in the graft at the time of transplantation are responsible for the induction of primary acute rejection. Experiments in the late 1970s have shown that F1 rat kidney allografts transplanted into a parental strain recipient under the cover of a short course of immunosuppression are not rejected when immunosuppression is withdrawn. When these allografts were retransplanted into a second parental strain, they were accepted in the absence of any immunosuppression.4 In contrast, if the retransplanted grafts were reconstituted with donor strain APCs, they were rejected at the same rate as primary grafts between the same donor and recipient strains.5 However, with time it becomes more difficult to induce acute rejection, even of grafts containing donor APCs, suggesting the emergence of a population of regulatory cells that maintain a state of tolerance.6 Based on these and other experiments, it has been proposed that engagement of recipient T-lymphocytes via their TCR␣/ V 0041-1345/99/$–see front matter PII S0041-1345(99)00787-3 16S
region with major histocompatibility complex (MHC) plus peptide on donor APCs induces an immune response that results in acute rejection, provided that the APCs deliver a second signal through one or more costimulatory molecules and growth-promoting cytokines are produced by the activated T-lymphocytes. Antigen presentation by donor APCs has been designated the direct route and is probably responsible for the early induction of a posttransplant immune response. On the other hand, direct recognition of graft parenchymal cells can induce donor-specific T-cell tolerance as graft parenchymal cells express donor antigens but do not provide costimulation.7 In addition to direct sensitization, there is evidence that donor antigens derived from APCs and parenchymal cells are also presented to the recipient immune system by recipient APC through the so-called indirect sensitization route.8 Donor antigens presented through the indirect route are taken up and processed by recipient APCs and presented to T-lymphocytes like any other nominal antigen. The indirect allosensitization route is likely to be important in chronic rejection. Defective APC-TCR interactions, lack of costimulation, or APC-TCR interactions in the presence of certain cytokines may result in tolerance.9,10 Furthermore, it has been suggested that tolerance induction depends on the establishment of a state of donor ‘microchimerism’11 which is the persistence of donor type hematopoietic cells in an allogeneic recipient. The precise mechanism by which microchimerism mediates prolonged graft survival is not clear, nor is it known what the relation is between these cells and the cells involved in induction of acute rejection. Great interest has emerged in posttransplant targeting of T-cell costimulatory pathways. Costimulators determine whether engagement of the TCR by MHC products will lead to activation, anergy, apoptosis, or neglect. In most models, blockade of the CD40/CD40L or B7/CD28 pathways separately prevents acute, but not chronic rejection,12,13 whereas simultaneous blockade of both pathways effectively aborts T-cell clonal expansion, promotes long-
From the Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands. Address reprint requests to L.C. Paul, MD, Department of Nephrology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail L.C.Paul@Nephrology. Medfac.LeidenUniv.nl. © 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 31 (Suppl 7A), 16S–17S (1999)
FUTURE OF NEW IMMUNOSUPPRESSIVE DRUGS
term survival of fully allogeneic grafts and inhibits chronic rejection.14,15 Kirk et al13 reported graft survival of ⬎180 days in a small series of Rhesus monkey renal transplants treated with a 28-day course of anti-CD40L monoclonal antibody and the CTLA4Ig fusion protein. Thus, simultaneous blockade of the CD40/CD40L and B7/CD28 pathways offers exciting clinical prospects. Many experimental forms of pretransplant tolerance induction have been proposed clinically. All protocols include pretransplant exposure to donor antigens with or without concomitant immunosuppression. In different models of rat renal16 or cardiac17,18 transplantation, such protocols prevent acute and chronic rejection, but their clinical applicability remains to be established.19
TISSUE CHANGES ASSOCIATED WITH GRAFT ACCEPTANCE
Most efforts to induce graft acceptance in the absence of continuous immunosuppressive medication have mainly focused on manipulation of the recipient immune system, while little attention has been given to the possibility of changing the graft’s resistance to injury. The observation that ABO-incompatible kidney grafts that survive the early posttransplant period continue to function despite the presence of high titers of antibodies against graft antigens led to the introduction of the concept of ‘graft adaptation,’20 the survival of an organ graft in the presence of antigraft antibodies and complement. While the proinflammatory response of, for example, endothelial cells following activation has been described extensively, less information is available regarding induction of tissue protective genes. Following cell activation, a number of genes are upregulated which protect the cell from apoptosis and suppress the proinflammatory response. A20 is a tissue protective gene that inhibits activation of NF-B, a transcription factor that plays a key role in the induction of proinflammatory events.21 Bcl-2 and Bcl-x are antiapoptotic genes, and hemoxygenase-1 (HO-1) prevents oxidant-stressed endothelial induction of adhesion molecules.22 HO-1 can also ameliorate tissue damage through the generation of heme breakdown products such as bilirubin, which exerts anticomplement or antioxidant effects, and carbon monoxide, which has vasodilatory and antiplatelet effects.23 The concept that tissue damage induces resistance to further injury was proposed as early as 1916 as an explanation for the observation that kidneys that recovered from uranium poisoning markedly resisted injury on further exposure. More recently it was shown that induction of the HO-1 gene using ferriprotoporphyrin IX chloride prior to induction of nephrotoxic serum nephritis has a protective effect on kidney function and structure.24 Upregulation of protective genes has been reported in grafts that are protected from hyperacute, acute and chronic rejection.25,26 Therefore, a goal for future immunosuppressive drugs is to induce sets of genes that protect the tissue against injury.
17S
FUTURE IMMUNOSUPPRESSIVE DRUGS
Immunosuppression should be based on an understanding of the immune response. While refining the intracellular target molecules of the various immunosuppressive drugs may create the potential to design agents that exert lymphocyte-selective immunosuppression without compoundspecific adverse events, the ultimate goal remains to be the establishment of donor-specific tolerance. New immunosuppressive drugs should prevent acute and chronic rejection while preserving immune responsiveness to viral, fungal, and tumor antigens. As not all graft inflammation results from immune reactions, future drugs should also inhibit graft recruitment of inflammatory cells that result from stimuli such as ischemia-reperfusion damage. Such treatment regimens should be devoid of intrinsic toxicity, easy to administer, affordable, and have no negative impact on quality of life.27 Finally, as the tissue reaction to damage is determined by its ability to resist injury, graft damage could be attenuated by manipulation of the graft to upregulate tissue protective genes.
REFERENCES 1. Halloran PF: Transplant Proc 28(suppl 1):11, 1996 2. Paul LC: Transplant Proc 30:4001, 1998 3. Sells RA: Transplant Proc 30(suppl 8A):14S, 1998 4. Batchelor JR, Welsh KI, Maynard A, et al: J Exp Med 150:455, 1979 5. Lechler RI, Batchelor JR: J Exp Med 155:31, 1982 6. Hall B, Jelbart K, Gurleyand K, et al: J Exp Med 162:1683, 1985 7. Frasca L, Marelli-Berg F, Imami N, et al: Kidney Int 53:679, 1998 8. Liu Z, Sun Y-K, Xi Y-P, et al: J Exp Med 177:1643, 1993 9. Madrenas J, Germain RN: Semin Immunol 8:83, 1996 10. Waldmann H, Cobbold S: Annu Rev Immunol 16:619, 1998 11. Starzl TE, Demetris AJ, Murase N, et al: Immunol Today 14:326, 1993 12. Larsen CP, Pearson TC: Curr Opin Immunol 9:641, 1997 13. Kirk AD, Harlan DM, Armstrong NN, et al: Proc Natl Acad Sci USA 94:8789, 1997 14. Larsen CP, Elwood ET, Alexander DZ, et al: Nature 381: 434, 1996 15. Subbotin V, Sun H, Chen C, et al: Transplant Proc 30:941, 1998 16. Sayegh MH, Perico N, Gallon L, et al: Transplantation 58:125, 1994 17. Orloff MS, DeMara EM, Coppage ML, et al: Transplantation 59:282, 1995 18. Shin YT, Adams DH, Wyner LR, et al: Transplantation 59:1647, 1995 19. Flye MW, Burton K, Mohanakumar T, et al: Transplantation 60:1395, 1995 20. Alexandre GPJ, Squifflet JP, De Bruyere M, et al: Transplant Proc 19:4538, 1987 21. Bach FH, Hancock WW, Ferran C: Immunol Today 18:483, 1997
18S 22. Bach FH, Ferran C, Soares M, et al: Nature Med 3:944, 1997 23. Willis D, Moore AR, Frederick R, et al: Nature Med 2:87, 1996 24. Mosley K, Wembridge DE, Cattell V, et al: Kidney Int 53:672, 1998
PAUL 25. Hancock WW, Buelow R, Sayegh MH, et al: Nature Med 4:1392, 1998 26. Soares MP, Lin Y, Anrather J, et al: Nature Med 4:1073, 1998 27. Kahan BD: Transplant Proc 30:2493, 1998