Immunotherapy in Transplantation And Autoimmunity
Stéphanie Bernardet
Research Scientist

Engineer

The research of Team 3 is situated in the « pre-clinical research » to « clinical development » frame. My research activity is dedicated to the control of humoral/ vascular rejection into allo- and xenotransplantation. In xenotransplantation we worked with a model of genetically modified donor pigs, using a same strategy than in allogenic humoral rejection, focusing on the blockade of the costimulation, of the antibody producing cells and of the complement cascade. We are also developing a new strategy of allo-graft pre-conditioning to achieve accommodation.

Description

The acute humoral rejection (AHR) is developed in vascularized organs, is induced by antibodies and has as consequences the endothelium damages and coagulation.

The AHR in kidney transplantation can be developed in 2 various situations: 1) recipient presents MHC incompatibilities with the donor and who develops donor specific anti-MHC allo-antibodies (DSA) in post-graft, and 2) recipients has already developed anti-MHC allo-antibodies prior transplantation (transfusions, pregnancies, previous allo-transplantation) and after a re-transplantation could reactivate memory cells producing DSA. These highly immunized patients constitute a growing patient population who present a higher risk to react against their donor and to develop AHR. In both cases, treatments fail to control AHR in ½ of cases.

Most of the strategies consist in recipient treatments. The main aim to achieve is the endothelial protection and we are working on strategies focusing on the blockade of the co-stimulation, of the antibody producing cells and of the complement cascade in a pre-clinical model of kidney transplantation in a context of allo-immunization.

In parallel, and in the same goal, we are also working on a second strategy in our pre-clinical model of kidney transplantation in allo-immunization context, more dedicated to highly immunized patients, focusing on the graft pre-conditioning before transplantation in order to induce the accommodation: a state of organ resistance to donor specific antibody (anti-ABO & -CMH) aggression.

These both strategies could also be conducted together.

The research in xenogeneic transplantation is the result of various points: the shortage of human organs and the availability of new molecular biology techniques applying to mammalians (transgenesis, cloning, gene therapy, chimerism). Then xenotransplantation becomes a research field allowing handling the problem in a new way. However xenotransplantation, by the existence of xeno-antigens (xenoAg) between various mammalian species, is still confronted to a humoral hurdle leading to acute humoral xenogeneic rejection (AHXR). Actually, the AHXR mechanism involves xenogeneic antigen (no MHC) recognition by pre-existing xenogeneic natural antibodies (XNA) leading to endothelium damages and coagulation, as AHR.

We are working in a pre-clinical model of kidney xeno- transplantation into 2 various strategies aiming the endothelium protection. The first one, similarly to AHR, consists in the blockade of the co-stimulation, of the antibody producing cells and of the complement cascade. In complementary manner, the second strategy focuses in the genetic modifications of donors targeting the xenoAg elimination, the control of the complement cascade and the coagulation and the thrombo-regulation.