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

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)