Organ transplantation has become the treatment of choice for end-stage organ failure. Despite modern immunosuppressive drug therapy, however, long-term graft survival remains limited. The induction of donor-specific immunological tolerance would be a solution to this problem.
We therefore aim to develop tolerance protocols that have the potential for improving outcome after organ transplantation.
The strategy we focus on is tolerance induction through mixed chimerism (i.e. coexistence of donor and recipient hematopoietic cells in the host established through the transplantation of donor bone marrow). This approach leads to a particularly robust state of tolerance and has been demonstrated to work not only in rodents, but also in large animals and notably in pilot series of renal transplant patients.
However, even though advanced experimental regimens for the induction of mixed chimerism have been developed, none is ready for widespread clinical translation due to toxicities associated with the necessary recipient conditioning. Our group is working on the development of novel protocols that avoid such toxicities and the delineation of the immunological mechanisms occurring in these models.
In addition, we are investigating the induction of tolerance in IgE-mediated allergy through molecular chimerism. In proof-of-principle studies the transplantation of syngeneic murine bone marrow retrovirally transduced to express a grass pollen allergen led to permanent molecular chimerism (i.e. persistence of hematopoietic cells expressing the allergen) and robust allergen-specific tolerance at the B cell, T cell and effector cell levels.
As long as tolerance induction is not feasible in the routine clinical setting, improved immunosuppressive drug therapy is an important goal. We therefore participate in the development of new immunosuppressive drugs and investigate their mechanisms of action. The new class of costimulation blockers is of particular interest to us, as they are also critical components of experimental tolerance protocols.