A single-dose, tolerizing vaccine induces antigen-specific regulatory T cells and durable remission while preserving healthy immunity in a mouse model of Multiple sclerosis
Journal of Immunology(2023)
摘要
Abstract Multiple sclerosis (MS) is an inflammatory disorder that occurs when autoreactive lymphocytes mistakenly attack myelin, resulting in motor deficits and cognitive deterioration. Current drugs are non-curative and require life-long treatment that make compliance challenging, and existing therapeutics can leave patients vulnerable to opportunistic infections. An experimental approach to overcome these hurdles is to drive long-lasting, antigen-specific regulatory T cells (Tregs) that dampen responses to autoantigens. Here, we co-deliver antigen and rapamycin in micron-sized, diffusion-limited, polymer microparticles (MPs) directly to lymph nodes (LNs) where immune responses are orchestrated. Using adoptive transfer of transgenic T cells, we show that MPs generate antigen-specific Tregs in response to two different MP-derived peptides – evidence that MPs do not interfere with induction of peripheral tolerance in LNs. In experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, single-dose treatment demonstrates potent, long-lasting efficacy (up to three months) following a single treatment. Tolerizing effects are observed during chronic disease – the most challenging for treatment regimens. Efficacy is accompanied by reduced demyelination in spinal cords of treated mice, the cause of paralysis in EAE and MS. Thus, antigen-specific reprogramming of Tregs in LNs reshapes inflammation in distal tissues without need for systemic or repeated dosing. Importantly, MP-treated EAE mice mount healthy immune responses to vaccine challenge. This work advances a strategy to locally reprogram antigen-specific, tolerogenic responses that preserve healthy immunity – a hurdle faced by current MS therapeutics. Supported by grants from NIH (R01 AI169686).
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关键词
multiple sclerosis,vaccine,healthy immunity,single-dose,antigen-specific
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