- Dr Christian Brander, Principal Investigator
- AIDS Research Institute Irsicaixa, Barcelona, Spain
- A Second Shot at HCV: The Impact of HLA Mismatch for Viral Control Post-OLT
End-stage liver disease due to Hepatitis C virus (HCV) infection often requires liver transplantation (OLT). The implanted organ is most often derived from a genetically unrelated (deceased) organ donor. From an immunological point of view, the implanted liver can thus be seen as a “foreign” organ in the transplanted organ recipient. As HCV infects the implanted liver, the new liver will present viral antigen on its surface to the host’s T cells and a second round of T cell responses to HCV may be induced. These HCV-specific T cells recognize viral antigen presented by so-called histocompatibility Leukocyte Antigens (HLA), a highly polymorphic group of human genes that specialize in antigen presentation to T cells. As donor and organ recipient are, in general, mismatched in their HLA genes, the T cells that existed in the organ recipient before the transplantation can no longer ‘see’ their viral antigen on the infected liver cells. Despite this quite evident limitation, essentially all studies that attempt to associate HCV-specific T cell-immunity with HCV-related liver-transplantation outcome have assessed these responses in vitro exclusively in the autologous setting (i.e. in the context of “self” HLA molecules, without using organ:donor-derived antigen presenting cells [APCs]). The hypothesis of the present application is that donor-HLA molecules on the implanted liver induce new T cell responses against HCV, which can help in the control of viral replication (as these T cells can actually ‘see’ the viral antigens on the infected new liver). The presence of these T cells will be assessed in two ways:
i) Based on a comprehensive screening using peptide sets spanning the entire HCV proteome, plus APCs derived from the organ donor, donor-HLA-restricted T cells will be stimulated, expanded and characterized.
ii) By comparing viral sequences before and after organ transplantation, specific mutations will be identified that could represent viral escape from donor-HLA-restricted T cell responses. Subsequent HLA footprint analyses, reverse genetics and traditional epitope-mapping studies will be used to demonstrate the existence of donor-HLA-restricted T cells to HCV post-transplantation.
A successful outcome of these studies would identify donor-HLA-restricted T cell responses as a potentially crucial parameter in the outcome of HCV-related liver transplantation. These findings would help to more effectively allocate scarce liver organs to the immunologically most suitable recipients and help further develop immune-based therapeutic interventions to improve liver transplantation outcome.