T cell depletion as a route to transplantation tolerance

Abstract

The aim of this work was that to investigate and possibly establish clinically-feasible therapeutic protocols in order to induce transplantation tolerance in solid organ (kidney) recipients. The model I adopted was that of murine skin transplantation across the complete MHC barrier, as it is known to be the most stringent model of organ transplantation, and the hardest barrier to overcome with a therapeutic treatment. My starting point was that T cell antibody depletion, currently utilized in the transplantation clinic as induction therapy, is effective and allows some reduction in maintenance immunosuppression, which is however still required life-long for the prevention of acute rejection. Therefore I sought to establish therapeutic protocols to induce transplantation tolerance building on the benefits of T cell depletion. I used as T cell depleting agent Campath-1, a powerful monoclonal lytic antibody, which is used for lymphocyte depletion in transplantation. The first strategy I developed was driven by the working hypothesis that the careful guidance of T cell reconstitution towards regulation could induce transplantation tolerance following depletion. Indeed the combination of an anti-IL-7R blocking antibody and Rapamycin could reduce the proliferation of effector T cells and favour the expansion of reconstituting Foxp3+ regulatory T cells, which are essential for tolerance. This combination treatment has succeeded at promoting indefinite survival of fully mismatched transplants, and graft acceptance so obtained proved to be dependent on TGF-ß signalling, as its neutralization limited graft survival. The second strategy I investigated relies on the knowledge that development of mixed haematopoietic chimerism following bone marrow transplantation can induce tolerance towards donor epithelial graft, but host myelo-ablation, required for bone marrow engraftment, remains a limiting factor for a wider application of this strategy into the clinic. I have developed for the first time a protocol based on T cell depletion, Rapamycin and co-stimulation antibody blockade that enables bone marrow engraftment without any need for myelo-ablation; mixed haematopoietic chimerism then induces transplantation tolerance towards epithelial graft of donor origin when performed later in time; tolerance so obtained is based on regulation as demonstrated by the phenomenon of linked-suppression. These results foster the concept that the adult immune system can be reprogrammed with a short-course treatment aimed at inducing tolerance towards not-self graft antigens; the clinical application of such tolerizing treatments will improve long-term transplantation outcomes, by limiting recipients exposure to the side effects inherent in life-long immunosuppression, currently required to prevent rejection.