Grant: CIHR Fellowship

Pathologies linked to end-stage organ failure represent the second cause of morbi-mortality worldwide and have major socio-economic consequences. Transplantation, which consists in the substitution of a defective organ by a functioning graft retrieved from a donor, is the best therapeutic option. Because the donor is from the same species but genetically different from the recipient, immune system of the latter inevitably recognizes donor-specific determinants expressed by the graft. The immune response that develops against donor-specific determinants is responsible for tissue damages, which lead to allograft dysfunction, a process called rejection. Organ damage is caused either by T lymphocytes, a process named cellular rejection, or by donor-specific antibodies(DSA), a process named antibody-mediated rejection (AMR). It is now widely acknowledged that AMR is the main cause of long-term organ loss. This is explained by the lack of reliable therapy to prevent DSA formation. Developing new approaches to prevent AMR has become one of the main challenge of transplantation medicine. Pr Levings' group (BC Children's Hospital Research Institute, Vancouver, where the project will take place) has just recently developed an innovative method of cell therapy to prevent allograft rejection. In this approach, recipient's T cells with tolerogenic properties (regulatory T cell, Treg) are genetically engineered to express a chimeric antigen receptor (CAR) and recognize donor-specific determinants. The group has obtained robust experimental evidence that these "educated" Treg have a remarkable ability to prevent cellular responses when transferred to recipients. In the present project, we will test for the first time the ability of donor-specific CAR Tregs to prevent AMR. We will try to potentiate inhibition of DSA formation through specific in vitro manipulations of CAR Tregs. This project could lead to a novel therapeutic approach to prevent antibody-mediated rejection.