HLA tissue compatibility in organ transplantation : from antigens to epitopes – EPIHLA

The HLA gene system (human leukocyte antigens) is extremely polymorphic (more than 20,000 proteins differing by at least one amino acid, distributed over 16 to 20 genes per genome) and is involved in the presentation of 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 the immunological rejection, especially in its humoral component. Rejection mediated by donor specific antibodies (DSA) is indeed not controlled by current immunosuppressive treatments. A DSA recognizes an allogeneic epitope on the surface of one or more HLA molecules, centered on an eplet, a donor polymorphism absent from the recipient. A patient's allelic serological profile is established against nearly 200 HLA alleles common in the "single antigen luminex" test. The donor/recipient compatibility for the transplant is estimated “only” at the scale of the entire molecule, the antigen, without taking into account these subtle variations which are the real causes of immunization. We will study HLA diversity to define eplets and epitopes, and the immunological properties of prototypes deemed representative (Bw4 / Bw6 eplet of HLA-A, -B and -C), and clinically major (HLA-DQ alleles) by combining several approaches: algorithmic analysis of a very large number of serum antibody profiles (from the national PHRC ACORGHLA project, NCT03861962), molecular modeling and structural superposition of these 200 alleles, study of the reactivity of sera against cells expressing a single HLA allele or a purposefully generated mutant, and the generation of human monoclonal antibodies from patients with DSA. We will also develop small competitors (single domain antibodies, or "nanobody") which could later find an application in the treatment / prevention of humoral rejection.