Study of Antigen Presentation and Antigen-Specific Immunomodulation in Multiple Sclerosis by T cell Receptor-Like Antibodies

The inhibition of inflammatory process during autoimmune diseases, such as Multiple Sclerosis (MS), is frequently achieved by non-specific down regulation of the immune system. Accordingly, targeted and specific inhibition of autoreactive T cells is highly desirable as a treatment for autoimmune disease. We hypothesize that during the inflammatory process in MS, APCs can present several myelin derived epitopes simultaneously and consequently activate a variety of autoreactive T cells. Accordingly, targeting one of these epitopes with T cell receptor like (TCRL) antibody (ab) could result in the elimination of specific APCs, thus prevent epitope spreading, decrease myelin-specific T cells` activation, affect differentiated T cell populations and most importantly decrease disease exacerbation. To this end, we have isolated and characterized TCRL Abs that are directed against MOG 35-55 or MBP 85-99/ HLA-DR2 epitopes. These TCRLs can obtain their function via two mechanisms of action: (i) block peptide-MHC interactions between pathogenic T cells and APCs, and (ii) specifically eliminate APCs that present MS-associated autoantigens. The TCRL Abs exhibit specific inhibition of T cell proliferation in vitro and in vivo. Moreover, treatment with TCRL of established EAE significantly attenuate disease progression and abolish EAE associated symptoms. In addition, administration of the TCRL prevent EAE development in HLA-DR2 Tg mice. These data demonstrate that targeting the core driving force of the immune response, the TCR-MHC axis, in an antigen-specific manner may lead to a new approach for immunotherapy of autoimmune diseases and other inflammatory disorders.