Transplantation tolerance through Treg therapy and chimerism

Inducing donor-specific tolerance in organ transplant recipients could improve long-term outcome which currently is unsatisfactory. Mixed chimerism established through transplantation of donor bone marrow (BM) is an appealing tolerance strategy. Its potential is underscored by recent pilot trials achieving operational tolerance in patients simultaneously receiving a BM and renal graft from the same donor. Widespread clinical application of this tolerance strategy is, however, prevented by the toxicity of the cytotoxic recipient conditioning which is required for achieving BM engraftment. Therefore, the development of tolerance protocols devoid of cytotoxicity (i.e. irradiation, cytotoxic drugs and antibodies) is an important research goal. In preliminary studies we demonstrated that the administration of recipient T regulatory cells (Tregs) together with rapamycin leads to engraftment of conventional doses of fully mismatched donor BM and to donor-specific skin graft tolerance without the need for cytotoxic recipient conditioning. This newly developed non-cytotoxic tolerance protocol provides the platform for the proposed translational studies. The overall objective of the project is to continue the in-depth investigation of this "Treg-chimerism protocol" and to develop it for clinical application for the purpose of tolerance induction in organ transplant recipients. The proposal addresses the three goals of the Translational Research Programme: 1. Strengthening of translational basic science at the interface with applied research: A strategy for clinical translation of the Treg-chimerism protocol is outlined, including pre-clinical testing in non-human primates; mechanistic questions will be investigated that are important for a detailed understanding of the model, aiding further development 2. Growth of human resources in science through the principle of "training through research": A PhD student will be working on a competitive topic in a research group with an established track record in training young scientists and will participate in the PhD program of the Medical University of Vienna. As PhD student Nina Pilat, a highly talented female scientist, developed the model on which this proposal is based. She will be able to stay in the applicant`s lab as post-doc, to continue developing her model and to actively promote her academic career. 3. Intensification of national collaborations and international networking: Long-standing national (Medical University of Innsbruck) and international (Harvard Medical School, Hannover Medical School) collaborations as well as newly established interactions (Medical University of Vienna) strengthen the proposed project. The project is expected to yield important mechanistic insight into the Treg-chimerism model and to develop it into a protocol ready for clinical testing. If successful, both the individual benefit to transplant patients and the societal gain would be significant.

The current project aims to improve long-term outcome after organ transplantation, which is at a high level but is nevertheless still suboptimal. Establishment of donor-specific immunological tolerance would be a potential solution to this pressing clinical problem. In this project we investigated a new tolerance protocol that combines two types of cell therapy (i.e. the infusion of donor bone marrow and so-called T regulatory cells (Tregs) that are important for down-regulating immune responses). This Treg-chimerism protocol is particularly promising as it does not require intense pre-treatment of the recipient. The results of this project determined the detailed biological mechanisms that are responsible for the tolerance achieved. Besides, the specific subtype of Tregs that leads to the best results was defined. Importantly, the data show how particularly effective the achieved tolerant state is, underlying the great potential of this new strategy. These results are important for planning the clinical translation of the Treg-chimerism strategy. If routine clinical application will eventually become reality in the future, the individual organ transplant patient would benefit through a better long-term result with fewer complications. Moreover, the gain for society would also be significant as transplanted organs would function longer and costs for immunosuppressive drugs would be saved.