Engineering the lymph node environment promotes antigen-specific efficacy in type 1 diabetes and islet transplantation.
Engineering the lymph node environment promotes antigen-specific efficacy in type 1 diabetes and islet transplantation.
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DOI：
10.1038/s41467-023-36225-5
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发表时间：
2023-02-08
影响因子：
16.6
通讯作者：
Jewell, Christopher M.
中科院分区：
文献类型：
--
作者：
Gammon, Joshua M.;Carey, Sean T.;Saxena, Vikas;Eppler, Haleigh B.;Tsai, Shannon J. J.;Paluskievicz, Christina;Xiong, Yanbao;Li, Lushen;Ackun-Farmmer, Marian;Tostanoski, Lisa H.;Gosselin, Emily A.;Yanes, Alexis A.;Zeng, Xiangbin;Oakes, Robert S.;Bromberg, Jonathan S.;Jewell, Christopher M.
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治疗的关键目标。这一结果可以选择性地抑制有害的炎症免疫反应，而不会损害功能保护性免疫。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不力，限制了疗效，并导致全身非特异性抑制。在这里，我们使用扩散受限的可降解微粒的淋巴内注射，这些微粒将自身抗原与免疫调节小分子雷帕霉素包裹在一起。我们发现这一策略在临床前1型糖尿病和同种异体胰岛移植中有效地抑制了疾病。最大的疗效需要抗原和雷帕霉素，耐受伴随着抗原特异性调节性T细胞在治疗和未治疗的淋巴结中的扩张。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，微粒治疗导致在淋巴结中形成耐受性结构微域。最后，淋巴结的这些局部结构和功能变化促进了抗原特异性调节性T细胞之间的记忆标记，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疗效。抗原特异性耐受是治疗1型糖尿病和同种异体胰岛移植排斥反应的一种有前景的策略。在这里，作者向淋巴结传递免疫信号，以促进抗原特异性调节性T细胞，并在1型糖尿病和同种异体胰岛移植模型中预防疾病。
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. Antigen-specific tolerance represents a promising strategy to treat type 1 diabetes and islet allograft rejection. Here, the authors deliver immune signals to lymph nodes to promote antigen-specific regulatory T cells and prevent disease in models of type 1 diabetes and allogenic islet transplantation.
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DOI：
10.1084/jem.20051954
发表时间：
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期刊：
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影响因子：
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作者：
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158.5
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DOI：
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发表时间：
2011-09-20
影响因子：
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