- Dr Maria-Luisa Alegre, Principal Investigator
- Dr Luciana Molinero, Research Associate
- Mr Jason Cosmano, Technician
- Mr Ying Wang, Microsurgeon
- The University of Chicago, Chicago, USA
- Treg Specificity in a Mouse Cardiac Transplantation Tolerance Model
Cardiac transplantation is the only cure for end-stage heart failure but T cell-dependent acute rejection of the transplanted organ invariably occurs in the absence of immunosuppression. Short-term treatment with drugs that prevent T cell activation during the peri-operative period can successfully lead to permanent acceptance of the graft in mice, and to a state of transplantation tolerance. We and others have shown that administration of anti-CD154 mAb in combination with donor-specific transfusion (DST) results in long-term acceptance of cardiac transplants and development of donor-specific tolerance. This tolerance correlates with the induction of donor-specific regulation, a phenomenon in which tolerant mice cannot reject a second transplant from a donor genetically identical to the original donor. This inhibition is mediated by regulatory T cells (Tregs), which suppress the function of graft-reactive T cells. In contrast, tolerant mice retain the ability to reject a second heart transplant from a mouse genetically distinct to the original-donor, suggesting that the immune system of the tolerant mouse is not globally immunosuppressed.
However, the mechanism by which tolerance becomes donor-specific is not clear and attempts at identifying the donor-reactive regulatory cells have been largely unsuccessful. Our preliminary results indicate that cardiac transplants in tolerant but not rejecting mice, attract Tregs that may be responsible for maintenance of tolerance. The surface molecules expressed on intragraft Tregs are different from those on Tregs from the spleen or lymph nodes, suggesting that a specific subset of Tregs is attracted to the tolerated graft. We hypothesize that intragraft Tregs are enriched in cells capable of suppressing the immune system in a donor-specific manner. In this project, we propose to test the specificity of the Tregs from the graft and sequence their antigen-recognition receptors.