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Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes

Abstract

A major challenge in transplantation medicine is controlling the very strong immune responses to foreign antigens that are responsible for graft rejection. Although immunosuppressive drugs efficiently inhibit acute graft rejection, a substantial proportion of patients suffer chronic rejection that ultimately leads to functional loss of the graft1. Induction of immunological tolerance to transplants would avoid rejection and the need for lifelong treatment with immunosuppressive drugs1,2. Tolerance to self-antigens is ensured naturally by several mechanisms3; one major mechanism depends on the activity of regulatory T lymphocytes4,5. Here we show that in mice treated with clinically acceptable levels of irradiation, regulatory CD4+CD25+Foxp3+ T cells stimulated in vitro with alloantigens induced long-term tolerance to bone marrow and subsequent skin and cardiac allografts. Regulatory T cells specific for directly presented donor antigens prevented only acute rejection, despite hematopoietic chimerism. By contrast, regulatory T cells specific for both directly and indirectly presented alloantigens prevented both acute and chronic rejection. Our findings demonstrate the potential of appropriately stimulated regulatory T cells for future cell-based therapeutic approaches to induce lifelong immunological tolerance to allogeneic transplants.

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Figure 1: In vitro–preactivated Foxp3+ Tregs induce long-lasting tolerance to fully allogeneic bone marrow grafts.
Figure 2: Tregs prevent acute and chronic skin allograft rejection.
Figure 3: Tregs prevent acute and chronic cardiac allograft rejection.

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Acknowledgements

The authors would like to thank M.-C. Cuturi, J. Cohen and C. Reis e Sousa for valuable advice and critical comments on the manuscript, J.-C. Guéry for stimulating discussions, F. Powrie (University of Oxford, UK) and R. Flavell (Yale University) for transgenic mice, the personnel of the Institut Fédératif de Recherche 30, Institut Fédératif de Recherche 31 and Institut de Pharmacologie et de Biologie Structurale animal facilities for expert animal husbandry, F. Capilla for preparation of histological specimens, the personnel of the Institut Fédératif de Recherche 30 flow cytometry facility for technical assistance, and C. Joffre for her permanent support. This work was supported in part by grants from the Région Midi Pyrénées (nos. 01008776 and 03011999), the Etablissement Français des Greffes (2003), the Roche Organ Transplantation Research Foundation (ROTRF no. 133456773) and the Ligue Nationale contre le Cancer (no. GL/VP-4825 to O.J.).

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Contributions

O.J. and T.S. performed, and contributed to the design of, the in vitro and in vivo experiments and interpreted results; D.C. designed and performed cardiac transplantations; T.A.S. helped in the design and interpretation of histological analysis; D.H. and P.R. contributed to the design of experiments and interpretation of results; J.P.M.v.M. directed the study and wrote the paper; and all authors contributed to writing and critically reviewing the manuscript.

Corresponding author

Correspondence to Joost P M van Meerwijk.

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Joffre, O., Santolaria, T., Calise, D. et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 14, 88–92 (2008). https://doi.org/10.1038/nm1688

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