Immunomodulation of EAE using CAR-T Cells that Target Autoreactive Epitopes

Autoimmune diseases are often mediated by abnormal activation of autoreactive CD4+ T cells. These cells interact with antigen presenting cells (APCs) that express disease associated autoantigens on MHC class II molecules in a pro-inflammatory context, thereby inducing an inflammatory response against self. Multiple sclerosis (MS) is a CD4+ mediated demyelinating autoimmune disease that is associated with HLA-DR2 MHC class II allele. Presentation of myelin associated epitopes, such as myelin oligodendrocyte glycoprotein (MOG) on HLA-DR2 by APCs in a pro-inflammatory context, results in autoreactive T cell activation and consequently nerve cells damage. Current MS treatments are based on immune response suppression and therefore development of antigen-specific treatments is highly desirable. The APC:T cell interactions are the core drivers of immune responses and also exhibit a specific check-point in the inflammatory process. Thus, we suggest that neutralization of myelin-associated epitopes presentation by APCs should decrease myelin-specific CD4+ T cell activation and consequently reduce inflammation during MS. Accordingly; we have isolated a T cell receptor like (TCRL) antibody that specifically targets and constructed second-generation chimeric antigen receptor (CAR) molecules based on its variable regions. specific CAR-CD8+ T cells successfully induced APCs death in vitro. We are currently conducting in-vivo experiments in experimental autoimmune encephalomyelitis diseased HLA-DR2 transgenic mice to assess the function of CAR-CD8+ T cells. These data may provide a proof of concept for the notion that elimination of disease-specific APCs by TCRL-based CAR-CD8+ T cells may serve as an antigen-specific therapeutic approach for autoimmune disease.