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 drugs^{1, 2}. Tolerance to self-antigens is ensured naturally by several mechanisms³; one major mechanism depends on the activity of regulatory T lymphocytes^{4, 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.

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 Meerwijk^1,2,5 e-mail: joost.van-meerwijk@toulouse.inserm.fr

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.

NPG Journals

by Subject Area

• Chemistry

  • Chemistry
  • Drug discovery
  • Biotechnology
  • Materials
  • Methods & Protocols

• Clinical Practice & Research

  • Cancer
  • Cardiovascular medicine
  • Dentistry
  • Endocrinology
  • Gastroenterology & Hepatology
  • Methods & Protocols
  • Pathology & Pathobiology
  • Urology

• Earth & Environment

  • Earth sciences
  • Evolution & Ecology

• Life sciences

  • Biotechnology
  • Cancer
  • Development
  • Drug discovery
  • Evolution & Ecology
  • Genetics
  • Immunology
  • Medical research
  • Methods & Protocols
  • Microbiology
  • Molecular cell biology
  • Neuroscience
  • Pharmacology
  • Systems biology

• Physical sciences

  • Physics
  • Materials

by A - Z Index