Abstract
Five decades of clinical transplantation have seen a dramatic improvement in many aspects of patient outcome, largely attributable to better quality immunosuppressive agents and their more judicious use. The success of contemporary immunosuppression is underscored by a reduction in the incidence of acute rejection rates between 1988 and 1998 from 60 to 20 percent and an improvement in one-year renal allograft survival rates to around 90 percent over the past 2 decades [1],[2]. Over the same period, despite substantial evidence implicating acute rejection as a major risk factor for chronic allograft nephropathy, the early benefits of our current immunosuppressive agents have not been maintained in the long-term. Historically, the immunosuppressive arsenal has encompassed predominantly steroid-based therapy initially and subsequently, the introduction of antimetabolites, calcineurin phosphatase inhibition, as well as antilymphocyte antibodies. Most of these agents are broadly acting and non-specific in their immunosuppressive effect. Consequently, these drugs have been associated with the spectrum of risks of global over-immunosuppression, including the development of life-threatening infectious complications and the increased risk of certain malignancies. Besides risk related to excessive immunosuppression, these medications have all been implicated in the plethora of serious non-immune related adverse effects, including perturbations in metabolic pathways (diabetes mellitus, osteopenia, hyperlipidemia), renal function (renal failure, hypertension), as well as several cosmetically disfiguring manifestations (weight gain, skin friability and bruising, hirsutism and alopecia).
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References
Cecka, J.M., The UNOS Scientific Renal Transplant Registry. Clinical Transplantation, 1997: p. 1–14.
United States Renal Data System, 1998 USRDS Annual Data Report, 1998, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD.
Janeway, C.H. and K. Bottomly, Signals and Signs for Lymphocyte Responses. Cell, 1994. 76: p. 275–285.
van Leeuwen, J.E. and L.E. Samelson, T cell antigen-receptor signal transduction. Curr Opin Immunol, 1999. 11(3): p. 242–248.
DeSilva, D.R., K.B. Urdahl, and M.K. Jenkins, Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation. J. Immunol., 1991. 147: p. 3261–3267.
Jenkins, M.K., et al., T cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol. Rev., 1987. 95: p. 113.
Noel, P.J., et al., CD28 costimulation prevents cell death during primary T cell activation. Journal of Immunology, 1996. 157: p. 636–642.
Bluestone, J.A., New perspectives of CD28-B7-mediated T cell costimultion. Immunity, 1995. 2(6): p. 555–559.
June, C.H., et al., The B7 and CD28 receptor families. Immunology Today, 1994. 15(7): p. 321–331.
Viola, A. and A. Lanzavecchia, T cell activation determined by T cell receptor number and tunable thresholds. Science, 1996. 273: p. 104–106.
Lee, K.M., et al., Molecular basis of T cell inactivation by CTLA-4. Science, 1998. 282(5397): p. 2263–2266.
Bluestone, J.A., Is CTLA-4 a master switch for peripheral T cell tolerance?. J. Immunol., 1997. 158(5): p. 1989–1993.
Krummel, M.F. and J.P. Allison, CTLA-4 Engagement Inhibits IL-2 Accumulation and Cell Cycle Progression upon Activation of Resting T Cells. J. Exp. Med., 1996. 183: p. 2533–2540.
Lin, H., et al., Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade accelerates the acute rejection of cardiac allografts in CD28-deficient mice: CTLA4 can function independently of CD28. J Exp Med, 1998. 188: p. 199–204.
Freeman, G.J., et al., Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. Science, 1993. 262: p. 907–909.
Sharpe, A.H., Analysis of lymphocyte costimulation in vivo using transgenic and ‘knockout’ mice. Curr Opin Immunol, 1995. 7(3): p. 389–395.
Schweitzer, A.N., et al., Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86. J Immunol, 1997. 158(6): p. 2713–2722.
Mandelbrot, D.A., et al., Expression of B7 molecules in recipient, not donor, mice determines the survival of cardiac allografts [In Process Citation]. J Immunol, 1999. 163(7): p. 3753–3757.
Shahinian, A., et al., Differential T cell costimulatory requirements in CD28-deficient mice. Science, 1993. 261: p. 609–612.
Kawai, K., et al., Skin allograft rejection in CD28-deficient mice. Transplantation, 1996. 61: p. 352–355.
Wu, Y., et al., CTLA-4-B7 interaction is sufficient to costimulate T cell clonal expansion. J Exp Med, 1997. 185: p. 1327–1335.
Durie, F.H., et al., The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunology Today, 1994. 15(9): p. 406–411.
Sayegh, M.H. and L.A. Turka, The role of T cell co-stimulatory activation pathways in transplant rejection. N Engl J Med, 1998. 338: p. 1813–1821.
Watts, T.H. and M.A. DeBenedette, T cell co-stimulatory molecules other than CD28. Curr Opin Immunol, 1999. 11(3): p. 286–293.
Liu, Y., et al., Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes. J Exp Med, 1997. 185: p. 251–262.
Lenschow, D., et al., Long-Term Survival of Xenogeniec Pancreatic Islet Grafts Induced by CTLA4Ig. Science, 1992. 257: p. 789–792.
Turka, L.A., et al., T cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci USA, 1992. 89: p. 11102–11105.
Linsley, P.S., et al., CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med, 1991. 174: p. 561–569.
Sayegh, M.H. and L.A. Turka, T cell costimulatory pathways: Promising novel targets for immunosuppression and tolerance induction. J Am Soc Nephrol, 1995. 6: p. 1143–1150.
Sayegh, M., et al., Donor antigen is necessary for the prevention of chronic rejection in CTLA4Ig-treated murine cardiac allografts. Transplantation, 1998. 64: p. 1646–1650.
Larsen, C.P., et al., Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature, 1996. 381: p. 434–438.
Wekerle, T., et al., Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J Exp Med, 1998. 187(12): p. 2037–2044.
Kirk, A., et al., CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc. Natl. Acad. Sci. (USA), 1997. 94: p. 8789–8794.
Kirk, A.D., et al., Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates [In Process Citation]. Nat Med, 1999. 5(6): p. 686–693.
Kenyon, N.S., et al., Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154. Diabetes, 1999. 48(7): p. 1473–1481.
Kenyon, N.S., et al., Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA, 1999. 96(14): p. 8132–8137.
Levisetti, M., et al., Immunosuppressive effects of hCTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation. J Immunol, 1997. 159: p. 5187–5191.
Guinan, E.C., et al., Transplantation of anergic histoincompatible bone marrow allografts. New England Journal of Medicine, 1999. 340(22): p. 1704–1714.
Abrams, J.R., et al., CTLA4Ig-mediated blockade of T cell costimulation in patients with psoriasis vulgaris. The Journal of Clinical Investigation, 1999. 103(9): p. 1243–1252.
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Bloom, R.D., Turka, L.A. (2001). Costimulation Blockade. In: Sayegh, M.H., Remuzzi, G. (eds) Current and Future Immunosuppressive Therapies Following Transplantation. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-1005-4_15
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DOI: https://doi.org/10.1007/978-94-010-1005-4_15
Publisher Name: Springer, Dordrecht
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