[856] Laboratory for Transplantation Immunology

The current organ shortage in transplantation medicine stimulates the exploration of new strategies to expand the donor pool including the utilization of living donors, ABO-incompatible grafts and possibly xenotransplantation. Our research focuses on:

1. Preformed natural antibodies, such as anti-A/B histo-blood group antibodies, mediate hyper-acute graft rejection in solid organ transplantation but do not seem to affect the outcome of hematopoietic stem cell transplantation (HSCT). Thus, ABO-incompatible HSCT may serve as an in vivo model to study the immunological mechanisms leading to successful carbohydrate-antigen mismatched transplantation. Our goal is to analyze the mechanisms such as deletion or anergy of B cells and understand the mechanisms of B cell tolerance induction in recipients of solid organ transplantation.

2. Cellular immune responses represent a major obstacle to successful transplantation. A major challenge in organ transplantation is to impair recipients'potential to reject the transplanted organ while preserving its function and limit the adverse effect of immunosuppression on patients' overall survival. The immunosuppressive regimens are mostly assessed on T and B lymphocytes but remain poorly explored with regard to post-transplant function and reconstitution of other immune effector cells, such as natural killer (NK) cells.

3. Porcine and human endothelial cells (EC) share the expression of receptors involved in the adhesion and transmigration of leukocytes into the graft. The interactions between human leukocytes and porcine EC depend on the existence of intact cross-species receptor-ligand interactions. Blocking of the crucial receptors for adhesion and transmigration, in combination with prevention of hyperacute rejection, may lead to the clinical feasibility of pig-to-human xenotransplantation. The goal of this project is to define the mechanisms of interactions between human leukocyte subsets and porcine EC in chemotaxis, adhesion, and transendothelial migration.

4. The induction of antigen-specific immunological tolerance, leaving the immune system intact, to prevent the cellular immune responses in transplantation is an attractive alternative for xenotranplantation. Naturally occurring CD4+CD25+Foxp3+ regulatory T (Treg) cells, contribute to immune regulation and tolerance induction in vivo. Treg cells showed suppressive function of self- and allo-reactive T effectors (Teff) cells in vitro and in vivo. However, the capacity of Treg to suppress the proliferation and Teff cells in response to xenogeneic cells is unknown. The aim of the present study is to investigate these mechanisms of tolerance in this xenogeneic islets transplantation model and to search the potential of ex vivo xenogeneic antigen specific Tregs in the induction of tolerance.

5. Infections represent a major cause of morbidity and mortality post-transplant. Human cytomegalovirus (CMV) establishes life-long latent infection and frequently reactivates in immuno-suppressed transplant recipients which potentially triggers graft rejection. The goal of these reserach is :

1) to elucidate the molecular effects of human CMV infection in porcine and human endothelial cells
2) the resulting influence on human leukocyte chemotaxis, adhesion and transmigration
3) the analyze of effector functions, in particular NK cell responses.

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