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      On the Horizon: Tailor-Made Immunosuppression in Renal Transplantation

      Nephron Clinical Practice

      S. Karger AG

      Immunosuppression, Kidney transplantation, Immunological tolerance

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          Immunosuppression for renal transplantation has undergone more changes over the last 8 years than at any other time in its history. It is now possible to be more selective in the matching of drugs with a given patient. This brings with it the option of improving graft outcome and also minimizing adverse effects. It is an ongoing process that will utilize agents working at different points in the activation cascade of the CD4+ ‘helper’ T lymphocyte. It may also be possible to manipulate the immune system such that the organ-specific immune response may be switched off, or rendered ‘tolerant’, thus removing the need for any immunosuppressive drugs. In this brief review, we shall address each of these approaches and discuss other therapeutic avenues being investigated.

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          Most cited references 8

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          Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance.

           L Turka,  Yu Li,  T Strøm (1999)
          The alloimmune response against fully MHC-mismatched allografts, compared with immune responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells. Thus, induction of peripheral allograft tolerance established in the absence of immune system ablation and reconstitution is a challenging task in transplantation. Here, we determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an essential initial step for induction of stable allograft tolerance with non-lymphoablative therapy. Blocking both CD28-B7 and CD40-CD40 ligand interactions (co-stimulation blockade) inhibited proliferation of alloreactive T cells in vivo while allowing cell cycle-dependent T-cell apoptosis of proliferating T cells, with permanent engraftment of cardiac allografts but not skin allografts. Treatment with rapamycin plus co-stimulation blockade resulted in massive apoptosis of alloreactive T cells and produced stable skin allograft tolerance, a very stringent test of allograft tolerance. In contrast, treatment with cyclosporine A and co-stimulation blockade abolished T-cell proliferation and apoptosis, as well as the induction of stable allograft tolerance. Our data indicate that induction of T-cell apoptosis and peripheral allograft tolerance is prevented by blocking both signal 1 and signal 2 of T-cell activation.
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            Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.

            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.
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              FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity.

              The novel immunomodulator FTY720 is remarkably effective in models of transplantation and autoimmunity. Recent data show that phosphorylated FTY720 is an agonist at four sphingosine 1-phosphate receptors. Stimulation of sphingosine 1-phosphate receptors leads to sequestration of lymphocytes in secondary lymphatic tissues and thus away from inflammatory lesions and graft sites.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                May 2003
                17 November 2004
                : 94
                : 1
                : c5-c10
                Faculty of Medicine, Imperial College London, Hammersmith Campus, London, UK
                70818 Nephron Clin Pract 2003;94:c5–c10
                © 2003 S. Karger AG, Basel

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                Figures: 1, Tables: 1, References: 13, Pages: 1
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