Study of antigen presentation and antigen-specific immunomodulation in multiple sclerosis by T cell receptor-like antibodies

Introduction. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) attacking approximately 2.5 million people worldwide. Symptoms include blurred vision, nausea and numbness and can deteriorate to complete loss of mobility and death. MS is characterized by distraction of the myelin tissue by auto-reactive CD4+ T cells: activation of CNS-infiltrating auto-reactive CD4+ T cells is triggered by the recognition of myelin-specific peptides presented on MHCII by antigen presenting cells (APCs), resulting in massive inflammation and consequently tissue damage.

Inhibition of inflammatory processes during MS is frequently achieved by non-specific down regulation of the immune system, which may lead to severe and potentially life-threatening side effects. Thus, targeted and specific inhibition of autoreactive CD4+ T cells is highly desirable as a treatment for MS and autoimmune diseases in general. We suggest that during inflammatory processes in MS, APCs can present several myelin derived epitopes (e.g. MOG and MBP) simultaneously and as a consequence activate a variety of autoreactive T cells. We therefore suggest that targeting one of these epitopes with a 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.

Materials and methods. We have isolated and characterized TCRL Abs directed against MOG (35-55) or MBP (85-99)/ HLA-DR2 epitopes. The potential mode of action of these antigen-specific TCRL Abs can be exerted via two mechanisms: (i) blocking the interactions between pathogenic T cells and their peptide-MHC ligands presented on APCs and (ii) specifically eliminate APCs presenting MS-associated autoantigens.

Results. The isolated TCRL Abs exhibit specific inhibition of T cell proliferation in vitro and in vivo. Moreover, treatment with a TCRL Ab of established EAE in HLA-DR2 Tg mice model significantly attenuate disease progression and abolish EAE associated symptoms. Additionally, administration of the TCRL prevents EAE development in these mice.

Conclusions. Our 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.