Immunological Tolerance Induced by Nanoliposome with Autoantigenie Peptide and Artesunate to Inhibit Complement and Remodel Immune Balance for Multiple Sclerosis Treatment.

Abstract

Multiple sclerosis (MS) is a demyelinating autoimmune disease (AD) accompanied by immune disorders and complement over activation. Although re-instatement of immune balance does alleviate MS symptoms, exploration of concomitant complement inhibition for neuron protection has not been evaluated. Herein, we developed myelin oligodendrocyte glycoprotein 35-55 (MOG) peptide and artemisinin (ART) co-loaded liposomes (MOG-ART-Lip) to simultaneously restore immune balance and inhibit complement activation. This nanoplatform enhanced solubility of both components while enabling CNS delivery. Liposomes loaded with MOG would induce tolerogenic DCs (tol-DCs) that express low-levels of costimulatory molecules, capable of antigenic peptide presentation and induction of regulatory T cells, while ART shifted microglia from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes. Importantly, ART suppressed complement-mediated demyelination via the C3/C3a receptor (C3aR) pathway. In vivo studies showed MOG-ART-Lip significantly reduced neuroinflammation, attenuated demyelination, and promoted neural repair, leading to functional recovery. Overall, results of this study suggest that a combination of an auto-antigenic peptide and an immune-modulator provides a promising modality for the treatment of MS by re-establishing antigen-specific immune tolerance. As such, the results of the study provide valuable insight into a new approach for development of combinatorial complement therapies for the treatment of MS patients.