Humanized Immune System mouse model for developing new therapeutic products and preclinical evaluation of vaccine and monoclonal antibodies candidates. – ImHIS

There is a critical need to screen and validate new vaccine candidates as immunotherapies for cancer, infection, and autoimmune disease. Recently, Human Immune System (HIS) reconstitution in immunodeficient mice has received renewed interest as a means to unravel the physiopathology of immune-related diseases and to predict effects on immune responses during the treatment of complex diseases. As such, HIS mice represent a particularly appropriate preclinical tool that can provide a cost effective and rapid alternative to small-scale clinical trials. This project has two specific aims: first, to optimize use of existing HIS mouse models for their use as preclinical vaccine testing tools; second, to create and validate novel HIS mouse models that address deficiencies in human MHC selection and peripheral MHC presentation via human dendritic cells (DC).
Productive immune responses are initiated by tissue patrolling DC that are activated in an inflammatory environment. The peptide determinants presented by surface MHC molecules on DC depend greatly upon the nature of the inflammatory conditions (composition of innate leucocytes, elaboration of soluble factors, …). The local ‘milieu’ subsequently conditions the acquisition and processing of antigen (Ag) that prime adaptive immunity upon migration of activated DC to the draining secondary lymphoid organs (SLO). While DCs are essential for the proper initiation of immune responses and Ag presentation, DC clearly act in concert with innate lymphocytes (including natural killer or NK cells) to set the response ‘rheostat’ or level that generates an optimal, long-lasting adaptive humoral and cellular immunity.
Although existing HIS mice generate a full repertoire of T and B cells (refs), HIS mice remain hyporesponsive with respect to primed immune responses (following immunization with commercial vaccines, for example) that may in part be due to suboptimal generation of human DCs and innate lymphocytes such as NK cells. In this proposal, these functional immune response defects will be corrected by several innovative approaches, including elimination of competition from host murine DCs (by ablation of the Flk2 growth factor receptor), by transgenic expression of human HLA-A2 molecules to improve NK and T cell education on human MHC, and by supplying growth factors to boost human DC, NK and T cell development and homeostasis (Flt3L and IL-15, respectively). The functional capacity of these ‘improved’ HIS mouse models to respond to antigenic and infectious challenges will be tested. Improved versions of humanized immune system mice will ultimately advance our understanding of human immune system diseases and may help devise more rational trials and streamline screening of therapeutic products.
Our ultimate aim to improve lymphocyte reconstitution and immune responses in HIS mice stems from our long-standing interest in lymphocyte development and our appreciation of the critical role of the immune system in protection against cancer and infectious diseases. The generation, validation and subsequent dissemination of HIS mouse model that can robustly ‘read-out’ human immune responses in vivo as a small animal model will provide an important tool for vaccine development to prevent or cure devastating diseases. Considering the central role for DCs in regulating immune responses through MHC/peptide recognition, the optimal generation of functional human DC in this mouse model and the selection and maintenance of T cells that have been ‘educated’ by human MHC would appear as necessary steps to fully realize the potential of this novel mouse model for understanding human diseases of the immune system and for developing novel immunotherapeutics for their treatment and cure.