EPIHLA2

The HLA (human leukocyte antigen) gene system is the most polymorphic (>20,000 proteins called HLA antigens, differing by at least one amino acid, distributed across 11 genes important in transplantation and grouped into 120 serological groups. It is involved in the presentation peptides to the T lymphocyte, a major player in the immune response. It is the human Major Histocompatibility Complex, responsible for the majority of losses of transplanted organs, via immunological humoral rejection. Rejection mediated by donor-specific antibodies (DSA) is in fact not controlled by current immunosuppressive treatments. A DSA recognizes an allogeneic epitope on the surface of one or more HLA antigens, centered on an eplet, a polymorphism of the donor absent from the recipient. The allelic serological profile of a patient is established against nearly 200 common HLA antigens using the “single antigen luminex” test. Donor/recipient compatibility for transplantation is estimated “only” at the serological group level, without taking into account the subtle variations in antigens which are the real causes of immunization. We will study HLA diversity to define eplets and epitopes, and the immunological properties of prototypes considered representative because they are clinically major (serological group A2, and HLA-DQ gene) by combining several approaches: the algorithmic analysis of a very large number of profiles serum antibodies (from the national ACORGHLA PHRC project, NCT03861962), molecular modeling and structural superposition of these 200 antigens, the study of the reactivity of sera against cells expressing a single HLA allele or a purposely generated mutant, and the generation of human monoclonal antibodies from patients carrying DSA. We will also develop small competitors (single domain antibodies, or “nanobody”) which could subsequently find an application in the treatment/prevention of humoral rejection. This project follows the ANR EPIHLA, period 2022-2025.