Antigen-Specific modulation of Chronic Experimental Autoimmune Encephalomyelitis in Humanized Mice by TCR-like Antibody Targeting Auto-Reactive T-Cell Epitope

Abstract

AbstractThe development and application of human T-cell receptor (TCR)-like antibodies (TCRL) recognizing disease-specific peptide-MHC complexes may prove an important tool for basic research and therapeutic applications.Multiple Sclerosis is characterized by aberrant CD4 T cell response to self-antigens presented by class II MHC molecules. This led us to select a panel of TCRL Abs targeting the immunodominant autoantigenic epitope MOG35-55 derived from Myelin Oligodendrocyte Glycoprotein (MOG) presented on HLA-DR2 which is associated with Multiple Sclerosis (MS).We demonstrate that these TCRL Abs bind with high specificity to human HLA-DR2/ MOG35-55 derived MHC class II molecules and can detect APCs that naturally present the MS-associated autoantigen in humanized EAE transgenic mouse model. The TCRLs can block ex vivo and in vivo CD4 T-cell proliferation in response to MOG35-55 stimulation in an antigen-specific manner. Most significant, administration of TCRL to MOG35-55 induced EAE model in HLA-DR2 transgenic mice both prevents and regresses established EAE. TCRL function was associated with reduction of autoreactive pathogenic T cells infiltration into the CNS, along with modulation of activated CD11b+ macrophages/microglia APCs.Collectively, these findings demonstrate the combined action of TCRL Abs in blocking TCR-MHC interactions and modulating APC presentation and activation, leading to a profound antigen-specific inhibitory effect on the neuroinflammatory process, resulting in regression of EAE.Our study constitutes an in vivo proof-of-concept for the utility of TCR-like antibodies as antigen-specific immunomodulators for CD4-mediated autoimmune diseases such as multiple sclerosis (MS), validating the importance of the TCR-MHC axis as a therapeutic target for various autoimmune and inflammatory diseases.