A Novel Nanoparticle Strategy to Stimulate Regulatory CD8 T Cells Directly In Vivo for the Treatment of Multiple Sclerosis 2258793

Abstract

Abstract Introduction We and others have described a regulatory CD8 T cell subset (CD8 Treg) restricted by nonclassical major histocompatibility complex Ib molecules, Qa-1 in mice and HLA-E in humans (collectively called Q/E). Previous studies from our laboratory and others have also shown that Q/E-restricted CD8 Treg can directly eliminate activated autoreactive, pathogenic CD4 T cells. However, the unknown identities of pathogenic T cells in human patients pose a significant barrier to the clinical translation of Q/E-restricted CD8 Treg. Methods To remove this barrier, we previously developed a novel technology to map Q/E epitopes in proteins. Using this new technology, we identified a peptide in myelin oligodendrocyte glycoprotein (MOG), MOG_OLP105, that stimulated both Qa-1- and HLA-E-restricted CD8 Treg. Additionally, immunization with activated dendritic cells (DCs) pulsed with MOG196, the optimal Qa-1 epitope in MOG_OLP105, significantly suppressed ongoing experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. However, DC-based therapy entails technological challenges and high costs. Here, we present a novel nanoparticle strategy that specifically targets DCs and delivers signals necessary to stimulate and expand myelin-specific, Q/E-restricted CD8 Treg directly in vivo. Results Our data showed that the DC-targeting nanoparticle specifically targeted and activated mouse and human DCs, accompanied by enhanced presentation of MOG196 and MOG_OLP105 by Qa-1 and HLA-E, respectively. DCs loaded with the nanoparticle stimulated autologous mouse and human CD8 T cells that suppressed the proliferation of autologous CD4 T cells in response to myelin antigens. Additionally, injection of the nanoparticle at disease onset led to a full recovery and induced resistance to disease reinduction. Furthermore, administering the nanoparticle at the peak of the disease also eliminates the disease. Conclusion Our data support the nanoparticle as a potential cure for multiple sclerosis. Funding Source Tang Gene Inc. Topic Categories Therapeutic Approaches to Autoimmunity (THER)