On the Horizon: Tailor-Made Immunosuppression in Renal Transplantation

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Abstract

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.

A Wells, X. Li, Y. Li … (1999)

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.

Volker Brinkmann, Kevin Lynch (2002)

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.

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Author and article information

Journal

Journal ID (publisher-id): NEC

Journal ID (nlm-ta): Nephron Clin Pract

Journal ID (doi): 10.1159/issn.1660-2110

Title: Nephron Clinical Practice

Publisher: S. Karger AG

ISSN (Electronic): 1660-2110

Publication date Subscription-year: 2003

Publication date (Print): May 2003

Publication date (Electronic): 17 November 2004

Volume: 94

Issue: 1

Pages: c5-c10

Affiliations

Faculty of Medicine, Imperial College London, Hammersmith Campus, London, UK

Article

Publisher ID: 70818 Other ID: Nephron Clin Pract 2003;94:c5–c10

DOI: 10.1159/000070818

PubMed ID: 12806186

SO-VID: 745e886a-0079-407c-b455-7e1f31ca49b9

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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On the Horizon: Tailor-Made Immunosuppression in Renal Transplantation

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Abstract

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Karger: Nephrology

Most cited references 8

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

Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.

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

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