ROTRF Recognition Prize – Recognising Excellence in Organ Transplantation Research

14:10: Prevention of Acute and Chronic Rejection of Skin and Heart Allografts with CD4+CD25+Foxp3+ Regulatory T Lymphocytes

Dr Joost van Meerwijk, Toulouse University, Toulouse, France

One of the major challenges in transplantation medicine is to control the very strong immune responses to foreign antigens responsible for graft-rejection. Whereas immunosuppressive drugs efficiently inhibit acute graft rejection, a non-diminishing proportion of patients suffers from chronic rejection, which ultimately leads to functional loss of the graft. Induction of immunological tolerance to transplants would avoid rejection and the need for lifelong treatment with immunosuppressive drugs. Tolerance to self-antigens is ensured naturally by several mechanisms, one of the major ones relying on the activity of regulatory T lymphocytes. In mice treated with clinically acceptable levels of irradiation, regulatory CD4+CD25+Foxp3+ T cells stimulated in vitro with alloantigens induced long-term tolerance to bone marrow and subsequent skin and cardiac allografts. Regulatory T cells specific for directly presented donor antigens prevented only acute rejection, despite hematopoietic chimerism. On the other hand, regulatory T cells specific for directly and indirectly presented alloantigens prevented both acute and chronic rejection. Transplanted mice rejected third party grafts and responded to immunization. They were therefore immunocompetent, confirming the specific nature of regulatory T cell-mediated immunosuppression. Persistence of the injected regulatory T cells was not required for maintenance of tolerance to bone marrow allografts. We are currently developing a drug-based preconditioning protocol to replace the low-level irradiation. Our findings demonstrate the potential of appropriately stimulated regulatory T cells for future cell-based therapeutic approaches to induce lifelong immunological tolerance to allogeneic transplants.

Joost van Meerwijk

Dr Joost van Meerwijk performed the work leading to his PhD degree in the laboratory of Dr. Michael Steinmetz at F. Hoffmann- La Roche Ltd in Basel. He then moved to the NIH in Bethesda where he worked as a post-doctoral fellow with Dr. Ronald Germain. His second post-doctoral period was spent at the Ludwig Institute for Cancer Research in Lausanne, Switzerland, in the group of Dr. Rob MacDonald. During his training, Dr. van Meerwijk worked on several aspects of thymic T cell development and induction of immunological tolerance to self-antigens. Since 1997, he holds a chair in Immunology at the University of Toulouse, France, and he heads a research laboratory at the INSERM, the "French NIH". His group works on intrathymic lineage commitment of regulatory T lymphocytes and the selection of their autospecific repertoire, on the physiological function of distinct regulatory T lymphocyte populations in the gut, and on the clinical potential of regulatory T cells in cellular immunotherapy against chronic allograft rejection.