Fischell Department of Bioengineering, University of Maryland, College Park, 8278 Paint Branch Drive, College Park, MD, 20742, USA.
Department of Surgery, University of Maryland Medical School, 22 S. Greene Street, S8B06, Baltimore, MD, 21201, USA.
Nat Commun. 2023 Feb 8;14(1):681. doi: 10.1038/s41467-023-36225-5.
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的实验性免疫治疗的关键目标。这种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免疫。抗原特异性免疫治疗面临的一个主要挑战是对免疫信号靶向和整合的控制效果不佳，限制了疗效并导致全身非特异性抑制。在这里，我们使用包封自身抗原和免疫调节小分子雷帕霉素的可扩散降解微球进行淋巴结内注射。我们表明，这种策略在临床前 1 型糖尿病和同种异体胰岛移植中能有效抑制疾病。抗原和雷帕霉素是最大疗效所必需的，并且在治疗和未治疗的淋巴结中都伴随着抗原特异性调节性 T 细胞的扩增。1 型糖尿病中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，微球治疗导致淋巴结中形成了免疫耐受的结构微区。最后，这些淋巴结中的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，并且这种耐受是持久的。这项工作支持淋巴结内注射免疫耐受微球作为一种强大的平台，以提高 1 型糖尿病和同种异体胰岛移植中抗原依赖性的疗效。
