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The Immuno-Hematology Research Unit (SRHI) created in 1991 further to the Chernobyl accident and at the request of the Haut-Commissaire à l’Energie Atomique J. TEILLAC, is in charge of the study of immune tolerance mechanisms of tissue grafts (solid and liquid), together with the immunological mechanisms for tumour escape from host surveillance. The research conducted by the SRHI since 1992 was behind the description of the function of the HLA-G molecule. The SRHI has thus established its position as the international leader on this subject, has federated numerous laboratories in several countries, and organised international conferences and workshops in 1998, 2000, 2003, 2006, 2009 and 2012 presided by E.D. Carosella.
HLA-G locking :
Restoration of polarization
The SRHI was created in 1991 at Saint-Louis Hospital (AP-HP) in order to benefit from close links with the university hospital and clinical expertise in cancerology and transplantation. The mission of the SRHI is to study immune tolerance mechanisms of tissue grafts, as well as tumor immune escape from host surveillance. It has conducted research on HLA-G, a non-classical HLA class I molecule, and its function since 1992.
SRHI team is composed of French university professors/hospital practitioners, foreign professors, researchers, pharmacy and medical residents, as well as graduates from the Grandes Ecoles in France.
In the 1990s, SRHI researchers were the first to demonstrate the immune tolerogenic function of the HLA-G molecule and its fundamental role in maternal-fetal tolerance. Indeed, HLA-G expression by the fertilized oocyte is essential to embryo implantation and proper development. Because maternal-fetal tolerance is a unique example of successful tolerance of allogeneic tissues, they hypothesized that HLA-G may also induce a state of tolerance in transplants. Thus, they first demonstrated the expression of soluble and membrane-bound HLA-G by allografts, and they showed that HLA-G exerts its tolerognic function by acting at all levels of the allogeneic reaction. Indeed, HLA-G inhibits the cytolytic function of NK cells, the antigen-specific cytolytic function of cytotoxic T lymphocytes (CTLs), the alloproliferative response of CD4+ T cells, and the maturation and function of dendritic cells.
Their work positioned HLA-G as a major immune checkpoint molecule with a broad immunoregulatory functions that affect both innate and adaptive immunity via its interaction with the inhibitory receptors ILT2 and ILT4, which are differentially expressed by immune cells. Thus, in contrast to both CTLA-4/B7 and PD1/PD-L1, the ILT/HLA-G checkpoint inhibits all actors, and blocks all stages of an immune response.
SRHI also developed studies in cancerology, a pathological context in which immune responses directed against the tumor are compromised. They first demonstrated that even though HLA-G is mostly expressed by fetal cells and not by adult tissues, it was neo-expressed to various degrees by most tumors. In this context, we demonstrated that HLA-G exerted its checkpoint immune inhibitory function and inhibited anti-tumor responses, thus causing immune escape. To develop translational studies in onco-uro-immunology, a translational group under the responsibility of Pr Desgrandchamps was created in 2013 within our team. This clinical group includes teams from :
Research's objective is to continue the research on the immune checkpoint molecule HLA-G in the context of transplantation and cancerology. At the fundamental level, SRHI aim at defining the link between HLA-G and other checkpoints, especially PD1/PDL1, and at understanding mechanisms controlling immune tolerance. Their final purpose is to go into clinical applications at the level of (i) therapy, by promoting tolerance mediated by HLA-G as anti-graft rejection strategy, while breaking down tolerance through anti-HLA-G for antitumor therapy, and (ii) monitoring, by identifying new markers for prognosis and treatment efficacy.
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