Lymph node depots exert local control over T cell fate to durably and safely reverse myelin-driven autoimmunity 3552

Abstract Description Multiple sclerosis (MS) is an inflammatory disorder that occurs when autoreactive lymphocytes mistakenly attack myelin, resulting in motor deficits and cognitive deterioration. Available therapies are non-curative, hindered by dose-limited toxicity and off-target effects that can leave patients vulnerable to opportunistic infections. Here, we co-deliver self-antigen and rapamycin in micron-sized, diffusion-limited, polymer microparticle (MP) depots directly to lymph nodes (LNs) to induce antigen-specific immune tolerance. In multiple preclinical MS mouse models, depots induced potent, long-lasting efficacy following a single administration during early, peak, or late-stage disease. Efficacy was accompanied by division of antigen-specific T cells and polarization of stable Tregs in response to depot-derived regulatory cues. Transcriptional analysis revealed altered signaling that controls T cell trafficking associated with elimination of spinal cord lesions. Importantly, treatment did not interfere with healthy T and B cell responses during vaccine challenge or impede peripheral tolerance. Lastly, LN depots exhibited favorable safety outcomes in non-human primates and an attractive chemistry and manufacturing control profile. This work advances a strategy where delivery of immunomodulatory cues to LNs through direct injection locally guides T cell fates, progressing the technology toward translation for treatment of autoimmune disease with antigen-specific selectivity. Funding Sources NIH/NIAID R01AI69686; NIH/NIBIB R01EB26896; NIH/NIAID R01AI144667 Topic Categories Therapeutic Approaches to Autoimmunity (THER)