Immunomodulation of EAE with Antibodies Targeting Autoreactive T-Cell Epitopes
Multiple sclerosis (MS) is a demyelinating autoimmune disease influencing more than 2.5 million people around the world. Damage caused in this disease, which is mediated by auto-reactive CD4+ T cells, disrupts nerve cell signaling, resulting in variety of symptoms, such as blurred vision, muscle stiffness and numbness. Previous studies suggested that human MS disease is associated with HLA-DR2 (DRB1*1501) MHC class II allele. Presentation of myelin associated epitopes, such as myelin oligodendrocyte glycoprotein (MOG) on HLA-DR2 by Antigen Presenting Cells (APCs) to autoreactive CD4+ T cells in a pro-inflammatory context, results in autoreactive T cell activation and consequently demyelination and nerve cells damage. Since MHC:TCR interaction is the immune response core driving force and is also the most specific check-point in the inflammatory process, targeting myelin associated epitopes presented in the context of MHC class II molecules by APCs may decrease myelin-specific autoreactive CD4+ T cell activation and consequently reduce the inflammatory process during MS. This goal may be achieved using T cell receptor like (TCRL) antibody- based (a) Chimeric Antigen Receptor (CAR) T cells, targeted against myelin associated epitopes presented by APCs, aiming for APCs destruction/suppression or (b) TCRL-PDL1 conjugated molecule, targeted against both PD1+ autoreactive T cells and myelin associated epitopes presented by APCs, delivering specific immune response attenuation against self, mediated by the TCRL arm, while inducing local autoreactive T cell inhibition via the PD-L1 arm. Accordingly, we have isolated and characterize TCRL antibodies with specificity toward MOG/DR2 epitope and tested their MS therapeutic effect as MOG/DR2-CAR-T cells and MOG/DR2-PDL1 bi-specific molecules. Our results suggests that anti-MOG/DR2-CD8+ CAR T cells show specific elimination of MOG/DR2 presenting APCs in-vitro, but exacerbate disease symptoms in-vivo, while anti-MOG/DR2 CAR T regulatory cells induce autoreactive T cell inhibition ex-vivo and should be further examined in-vivo. Also, administration of anti-MOG/DR2-PDL1 bi-specific molecules induce target-specific autoreactive T cell inhibition ex-vivo but shows inconclusive results in-vivo and accordingly should be further optimized and examined as MS therapeutic tool.
