Significance and goal of our research
Solid organ transplantation necessitates the administration of non-specific immunosuppressive treatments. In some patients, these only imperfectly prevent graft rejection and can have severe side effects. Alternative treatments that induce specific tolerance to the graft are thus desirable. The goal of our project is to test this possibility by using a population of immunoregulatory CD4⁺CD25⁺ T cells (T_reg) that we and others have shown to be involved in the regulation of auto-immune diseases and graft-versus-host disease.

How can our goal be reached?
After transplantation, alloantigens (histocompatibility antigens) from the graft are presented either by donor (direct pathway) or recipient (indirect pathway) antigen- presenting cells. Indirect evidence suggests that prevention of allograft rejection by T_reg may be achieved by using cells previously selected to recognize specifically donor-type alloantigens through the direct and/or indirect pathways. In preliminary experiments, we were able to expand and select in vitro T_reg specific for alloantigens presented by the direct pathway that function in vivo to induce specific tolerance. In our research proposal, we will optimize this culture and set up new conditions for the generation of T_reg specific for alloantigens presented by the indirect pathway. These two types of T_reg will then be tested in parallel for their ability to control allograft rejection in mouse models of skin and islet transplantation. All these culture conditions should be transferable to the human setting. Thus, we will adapt the protocol for in vitro selection of alloantigen-specific T_reg in humans.

Possible impact of our research in medicine
The generation of alloantigen-specific T_reg may be used in the future in organ transplantation to induce long-term acceptance of the graft. This new therapeutic strategy may allow a reduction in the doses of the immunosuppressive drugs, thus limiting adverse events.