Letter abstract


Nature Medicine 14, 88 - 92 (2008)
Published online: 9 December 2007 | doi:10.1038/nm1688

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

Olivier Joffre1,2,6,7, Thibault Santolaria1,2,6, Denis Calise3, Talal Al Saati4, Denis Hudrisier1,2,7, Paola Romagnoli1,2 & Joost P M van Meerwijk1,2,5

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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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  1. Institut National de la Santé et de la Recherche Médicale, U563, Tolerance and Autoimmunity section, Toulouse, F-31300 France.
  2. Université Toulouse III Paul Sabatier, Toulouse, F-31400 France.
  3. Institut National de la Santé et de la Recherche Médicale, Institut Louis Bugnard, Institut Fédératif de Recherche 31, Plateau technique de Microchirurgie Expérimentale, Toulouse, F-31403 France.
  4. Institut National de la Santé et de la Recherche Médicale, Institut Claude de Preval, Institut Fédératif de Recherche 30, Plateau technique d'Histopathologie Expérimentale (Toulouse Midi-Pyrénées Genopole), Toulouse, F-31300 France.
  5. Institut Universitaire de France, Paris, F-75000 France.
  6. These authors contributed equally to this study.
  7. Present addresses: Cancer Research UK London Research Institute, Immunobiology Laboratory, London WC2A 3PX, UK (O.J.); Centre National de la Recherche Scientifique, UMR5089, Institut de Pharmacologie et de Biologie Structurale, Toulouse, F-31400 France (D.H.).

Correspondence to: Joost P M van Meerwijk1,2,5 e-mail: joost.van-meerwijk@toulouse.inserm.fr



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