Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific.
Reprogramming the Local Lymph Node Microenvironment Promotes Tolerance that Is Systemic and Antigen Specific.
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DOI：
10.1016/j.celrep.2016.08.033
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发表时间：
2016-09-13
期刊：
影响因子：
8.8
通讯作者：
Jewell CM
中科院分区：
文献类型：
--
作者：
Tostanoski LH;Chiu YC;Gammon JM;Simon T;Andorko JI;Bromberg JS;Jewell CM
许多自身免疫性疾病的实验性疗法，如多发性硬化症（MS），旨在使T细胞偏向于耐受性表型，而不广泛抑制。然而，淋巴结局部信号整合与全身耐受特异性之间的联系尚不清楚。我们使用LN内注射聚合物颗粒来研究LN微环境中信号的耐受性。在小鼠MS模型中，在ln内引入包裹髓磷脂自身抗原和调节信号（雷帕霉素），在疾病高峰期进行一次治疗后，永久性地逆转了瘫痪。治疗效果是髓磷脂特异性的，需要抗原包封，没有雷帕霉素的效果较弱。这种疗效伴随着局部LN重组、炎症减轻、调节性T细胞的全身扩张和T细胞向中枢神经系统的浸润减少。我们的研究结果表明，对不同LNs信号传导的局部控制可以促进细胞类型和功能，从而驱动系统性的抗原特异性耐受性。Tostanoski等人的研究表明，在髓磷脂攻击的多发性硬化症小鼠模型中，单次直接向小鼠淋巴结注射可降解颗粒可逆转瘫痪。这种局部淋巴结微环境对调节功能的重编程驱动了系统性但髓磷脂特异性的耐受性。
Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells towards tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin) permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin-specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the central nervous system. Our findings suggest local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic, but antigen-specific. Tostanoski et al. show that a single direct injection of degradable particles into mouse lymph nodes reverses paralysis in a mouse model of multiple sclerosis underpinned by myelin attack. This local reprogramming of the lymph node microenvironment towards regulatory function drives tolerance that is systemic but myelin-specific.
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影响因子：
17.1
作者：
Hunter Z;McCarthy DP;Yap WT;Harp CT;Getts DR;Shea LD;Miller SD
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1408686111
发表时间：
2015-01-13
影响因子：
11.1
作者：
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作者：
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