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Dominant Tolerance to Kidney Allografts Induced by Anti-Donor MHC Class II Antibodies: Cooperation between T and Non-T CD103⁺ Cells

Nicolas Degauque^*,, David Lair^*,, Alexandre Dupont^*,, Anne Moreau, Gwénaelle Roussey^*,, Frédérique Moizant^*,, François Xavier Hubert^*,, Cédric Louvet^*,, Marcelo Hill^*,, Fabienne Haspot^*,, Régis Josien^*,, Claire Usal^*,, Bernard Vanhove^*,, Jean Paul Soulillou^1,2,*, and Sophie Brouard^2,*,

^* Institut National de la Santé et de la Recherche Médicale–Université de Nantes, Unité Mixte de Recherche 643, Nantes, France; and Immunointervention dans les allo et Xenotransplantations and Institut de Transplantation et de Recherche en Transplantation and Pathology Laboratory, Centre Hospitalier Universitaire-Hotel Dieu, Nantes, France

Allograft acceptance can be induced in the rat by pretransplant infusion of donor blood or spleen cells. Although promoting long-term acceptance, this treatment is also associated with chronic rejection. In this study, we show that a single administration of anti-donor MHC class II alloimmune serum on the day of transplantation results in indefinite survival of a MHC-mismatched kidney graft. Long-term recipients accept a donor-type skin graft and display no histological evidence of chronic rejection. The kidney grafts of tolerant animals display an accumulation of TCR C, FoxP3, and IDO transcripts. Moreover, as compared with syngeneic recipients, tolerant recipients harbor a large infiltrate of MHC class II⁺ cells and CD103⁺ cells. In vitro, splenocytes from tolerant recipients exhibit decreased donor-specific proliferation, which is restored by depletion of non-T cells and partially restored by the blockade of IDO. Finally, splenocytes from tolerant recipients, but not purified T cell splenocytes, transfer donor-specific infectious tolerance without chronic rejection, after infusion into naive recipients, over two generations. However, splenocytes depleted of T cells or splenocytes depleted of CD103⁺ cells fail to transfer tolerance. Collectively, these data show that a single administration of anti-donor MHC class II alloimmune serum induces a tolerant state characterized by an infiltration of the kidney graft by regulatory T cells and CD103⁺ cells. These data also show that the transfer of tolerance requires the presence of both T cells and CD103⁺ dendritic cells. The precise mechanism of cooperation of these two cell subsets remains to be defined.

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