Clinical Immunology; Costimulatory and Inhibitory T-Cell Receptors; Immunosuppression; Models, Animal; Models, Immunological; T-Lymphocytes, Regulatory; Translational Medical Research; Transplantation; Transplantation Chimera; Transplantation Immunology; Transplantation Tolerance
The main goal of our research is the intentional establishment donor-specific immunological tolerance to avoid the problems and risks associated with lifelong treatment of organ transplant recipients with immunosuppressive drugs.
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 numerous 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 advanced protocols for the transplantation of allogeneic hematopoietic cells and the delineation of the immunological mechanisms occurring in these models. To this end, we have recently developed a minimally toxic tolerance protocol that combines T regulatory cell theapy with allogeneic bone marrow transplantation.
Moreover, we investigate the use of costimulation blockers and their immunosuppressive and tolerogenic mechanisms of action.
Techniques, methods & infrastructure
In vivo mouse models of bone marrow transplantation (allogeneic combinations with defined minor and major antigen disparities; CD45.1/2 congeneic combinations), heart transplantation (heterotopic, cervical) and skin transplantation. T regulatory cell transfer in mice. Various in vitro assays for measuring alloreactivity (proliferation assays, suppression assays, donor-specific antibody measurement).
Sykes, M. et al., 2000. Nat. Med., 6(4), pp.464-469. Available at: dx.doi.org/10.1038/74731.
Blaha, P., 2002. The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade. Blood, 101(7), pp.2886-2893. Available at: dx.doi.org/10.1182/blood-2002-10-3014.
Vincenti, F. et al., 2005. Costimulation Blockade with Belatacept in Renal Transplantation. N Engl J Med, 353(8), pp.770-781. Available at: dx.doi.org/10.1056/NEJMoa050085.
Baranyi, U. et al., 2008. Tolerization of a Type I Allergic Immune Response through Transplantation of Genetically Modified Hematopoietic Stem Cells. The Journal of Immunology, 180(12), pp.8168-8175. Available at: dx.doi.org/10.4049/jimmunol.180.12.8168.
Pilat, N. et al., 2010. Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning. American Journal of Transplantation, 10(4), pp.751-762. Available at: dx.doi.org/10.1111/j.1600-6143.2010.03018.x.