Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation.

抗原特异性耐受是自身免疫性疾病和同种异体移植排斥实验免疫疗法的一个关键目标。这一结果可以选择性地抑制有害的炎症免疫反应，而不损害功能性保护性免疫。抗原特异性免疫疗法面临的主要挑战是对免疫信号靶向和整合的无效控制，限制了疗效并导致系统性非特异性抑制。在这里，我们使用淋巴结内注射限制扩散的可降解微粒，将自身抗原与免疫调节小分子雷帕霉素封装起来。我们证明这种策略可以有效抑制临床前 1 型糖尿病和同种异体胰岛移植期间的疾病。抗原和雷帕霉素是发挥最大功效所必需的，耐受性伴随着治疗和未治疗淋巴结中抗原特异性调节性 T 细胞的扩增。 1 型糖尿病的抗原特异性耐受是全身性的，但避免了非特异性免疫抑制。此外，微粒治疗导致淋巴结中产生耐受性结构微区。最后，淋巴结中的这些局部结构和功能变化促进了抗原特异性调节性 T 细胞中的记忆标记，以及持久的耐受性。这项工作支持淋巴结内注射耐受性微粒作为一个强大的平台，以促进 1 型糖尿病和同种异体胰岛移植的抗原依赖性功效。