The indispensable lifelong treatment with immunosuppressive drugs is only partially effective in inhibiting chronic graft loss and is accompanied by severe side effects (e.g. infections, malignancies). Therefore, the intentional establishment donor-specific immunological tolerance remains a primary goal for transplantation research.
We focus on inducing tolerance through the transplantation of donor hematopoietic stem cells and the establishment of mixed chimerism (i.e. coexistence of donor and recipient hematopoietic cells in the host). This strategy leads to a particularly robust state of tolerance and has been demonstrated to work not only in rodents, but also in large animals (including non-human primates) and notably in pilot series of renal transplant recipients in the clinic.
However, even though ever milder experimental regimens for the induction of mixed chimerism have been developed, none is ready for widespread clinical translation due to remaining toxicities. Our group is working on the development of refined protocols for the transplantation of allogeneic hematopoietic cells and the delineation of the immunological mechanisms occurring in these models. Moreover, we investigate the use of costimulation blockers and their immunosuppressive and tolerogenic mechanisms of action.
An additional focus lies in the delineation of the pathophysiological mechanisms of a novel subtype of donor-specific antibodies that we have recently defined in the pre-clinical and clinical setting.
We are investigating the induction of tolerance in IgE-mediated allergy through cell therapy. 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.
Until tolerance will have become reality in the routine clinical setting, immunosuppression remains a critical factor determining post-transplant outcome and hence its further improvement is an important medical need.
We participate in industry-sponsored phase II, III and IV trials of immunosuppressive drug therapy and immunological diagnostics in kidney and liver transplantation. Moreover, we perform investigator-initiated clinical studies, focusing on the mechanisms of action of immunosuppressive drugs (in particular costimulation blockers) and on the development of immunomonitoring strategies with the ultimate goal of allowing personalized immunosuppressive drug therapy.