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Importance of ICOS–B7RP-1 costimulation in acute and chronic allograft rejection

Nature Immunology volume 2, pages 591–596 (2001)Cite this article

Abstract

Primary T cell activation requires B7-CD28 and CD40-CD154 costimulation, but effector T cell functions are considered to be largely independent of these costimulatory pathways. Although blockade of costimulation with cytolytic T lymphocyte–associated antigen 4–immunoglobulin (CTLA-4–Ig) or monoclonal antibody (mAb) to CD154 prolongs allograft survival, chronic rejection follows, which suggests that additional key costimulatory pathways are active in vivo. We found that both antibody to inducible costimulator (anti-ICOS) and an ICOS-Ig fusion protein suppressed intragraft T cell activation and cytokine expression and prolonged allograft survival in a manner similar to that in ICOS−/− allograft recipients. The combination of anti-ICOS therapy and cyclosporin A led to permanent engraftment. In addition, ICOS–B7RP-1 costimulation was required for the development of chronic rejection after CD40-CD154 blockade. These data demonstrate a key role for the ICOS–B7RP-1 pathway in acute and chronic rejection and highlight the benefits of targeting this pathway in combination with the use of conventional immunosuppressive agent.

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Figure 1: Up-regulation of ICOS, but not B7RP-1, during acute rejection.
Figure 2: Blockade of ICOS–B7RP-1 costimulation inhibits acute allograft rejection.
Figure 3: Blockade of ICOS–B7RP-1 costimulation preserves graft histology.
Figure 4: Blockade of ICOS–B7RP-1 costimulation blocks intragraft immune activation.
Figure 5: ICOS-dependent chronic rejection after anti-CD154 therapy.
Figure 6: Synergistic effect of CsA therapy and targeting ICOS–B7RP-1.

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Acknowledgements

Supported by a National Institutes of Health grant AI40152 (to W. W. H.).

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Authors and Affiliations

  1. Millennium Pharmaceuticals, Inc., 75 Sidney Street, Cambridge, 02139, MA, USA

    Engin Özkaynak, Wei Gao, Nida Shemmeri, Chichung Wang, Jose-Carlos Gutierrez-Ramos, Jillian Amaral, Shixin Qin, James B. Rottman, Anthony J. Coyle & Wayne W. Hancock

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  1. Engin Özkaynak
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Correspondence to Wayne W. Hancock.

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Özkaynak, E., Gao, W., Shemmeri, N. et al. Importance of ICOS–B7RP-1 costimulation in acute and chronic allograft rejection. Nat Immunol 2, 591–596 (2001). https://doi.org/10.1038/89731

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