Induction of Tolerance: Mechanisms and Implications for Clinical Transplantation

Therapies that promote tolerance will improve outcomes in solid organ transplantation by eliminating the need for long-term immunosuppression. This thesis investigates two possible tolerance induction mechanisms: rapamycin induced expression of regulatory T cells and re-education of the immune system using syngeneic hematopoietic stem cell transplantation. Fibrinogen-like protein 2, a effector molecule of regulatory T cells, was also determined as a key mediator in the tolerance induction pathway as depletion of fibrinogen-like protein 2 lead to allograft rejection. The feasibility of using syngeneic hematopoietic stem cells for inducing allograft tolerance was studied by setting up a murine heart and bone marrow transplant model. Syngeneic T-depleted bone marrow transplantation resulted in a slight prolongation of the graft survival time compared to the animals reconstituted with total bone marrow cells. We provide compelling evidence to suggest that fibrinogen-like protein 2 and syngeneic hematopoietic stem cells can possibly be used to induce transplantation tolerance.MAS