Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes.
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 graft. Induction of immunological tolerance to transplants would avoid rejection and the need for lifelong treatment with immunosuppressive drugs. Tolerance to self-antigens is ensured naturally by several mechanisms; one major mechanism depends on the activity of regulatory T lymphocytes. 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.
Institut National de la Santé et de la Recherche Médicale, U563, Tolerance and Autoimmunity section, Toulouse, F-31300 France.
Olivier
O
Joffre
Thibault
T
Santolaria
Denis
D
Calise
Talal
T
Al Saati
Denis
D
Hudrisier
Paola
P
Romagnoli
Joost P M
JP
van Meerwijk
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D007519:Isoantigens / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000379:methods*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens