CD4 + CD25 + Regulatory T Cell Therapy for the Induction of Clinical Transplantation Tolerance

Abstract

The pursuit of transplantation tolerance is still in progress some 53 years after Medawar and colleagues’ first description. It has been established beyond doubt that regulatory T cells can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex-vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. This technique has been used to demonstrate long term graft survival in mouse models, where ex-vivo expanded, alloantigen specific T cells are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. When such models are selected to test the role of the different allorecognition pathways for Treg induced graft survival, it appears that only a modest direct pathway alloresponse is sufficient to abrogate tolerance in immunocompetent mice. This remains the case when Tregs are expanded with both direct and indirect pathway allospecificity. Therefore, in human transplantation it is likely that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex-vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, while they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made in the last few years to define which immunosuppressive drugs favour the expansion and function of Tregs. It is proposed that a trial of Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression is on the near horizon for human transplantation.