Coupling of peripheral tolerance to endogenous interleukin 10 promotes effective modulation of myelin-activated T cells and ameliorates experimental allergic encephalomyelitis
Coupling of peripheral tolerance to endogenous interleukin 10 promotes effective modulation of myelin-activated T cells and ameliorates experimental allergic encephalomyelitis
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DOI：
10.1084/jem.191.12.2039
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发表时间：
2000-06-19
影响因子：
15.3
通讯作者：
Zaghouani, H
中科院分区：
文献类型：
--
作者：
Legge, KL;Min, B;Zaghouani, H
一些基于免疫的方法正在考虑用于调节炎性T细胞和改善自身免疫性疾病，最新的策略包括通过注射无佐剂抗原模拟外周自身耐受，通过遗传改变的T细胞局部递送细胞因子，以及干扰共刺激分子的功能。尽管从这些研究中已经获得了有希望的结果，这些研究定义了T玩偶调节、功效、实用性和毒性的机制，但问题仍然没有解决，从而证明了进一步研究以定义有效下调侵袭性T细胞的替代方案的合理性。在先前的研究中，我们证明了携带致脑炎蛋白脂质蛋白（PLP）1肽的免疫球蛋白（IG）嵌合体（对应于PLP的氨基酸序列139-151，Ig-PLP 1）呈递给T细胞的效果比游离PLP 1好100倍。在这里，我们证明，聚集赋予Ig-PLP 1的一个额外的功能，即，诱导白细胞介素（IL）-10生产的巨噬细胞和树突状细胞，这两个aro抗原呈递细胞（APC）。这些功能在体内协同作用并驱动自身免疫的有效调节。事实上，已经表明，当用无佐剂的聚集Ig-PLP 1治疗时，患有持续活动性实验性过敏性脑脊髓炎的动物显著降低了其瘫痪的严重程度。此外，IL-10在无关的自身反应性T玩偶上显示旁观者拮抗作用，允许逆转涉及多个表位的疾病。因此，聚集的Ig-PLP 1可能将源自表达次优共刺激分子的APC的肽呈递和IL-10旁观者抑制的外周T细胞耐受机制结合在一起，以驱动双模式T细胞调节系统，其有效逆转涉及几个表位和不同T细胞特异性的自身免疫。
Several immune-based approaches are being considered for modulation of inflammatory T cells and amelioration of autoimmune diseases, the most recent strategies include simulation of peripheral self-tolerance by injection of adjuvant free antigen, local delivery of cytokines by genetically altered T cells, and interference with the function of costimulatory molecules. Although promising results have been obtained from these studies that define mechanisms of T doll modulation, efficacy, practicality, and toxicity, concerns remain unsolved, thereby justifying further investigations to define alternatives for effective downregulation of aggressive T cells. In prior studies, we demonstrated that an immunoglobulin (Ig) chimera carrying the encephalitogenic proteolipid protein (PLP)1 peptide corresponding to amino acid sequence 139-151 of PLP, Ig-PLP1, is presented to T cells similar to 100-fold better than free PLP1. Here, we demonstrate that aggregation endows Ig-PLP1 with an additional feature, namely, induction of interleukin (IL)-10 production by macrophages and dendritic cells, both of which aro antigen presenting cells (APCs). These functions synergize in vivo and drive effective modulation of autoimmunity. Indeed, it is shown that animals with ongoing active experimental allergic encephalomyelitis dramatically reduce the severity of their paralysis when treated with adjuvant free aggregated Ig-PLP1. Moreover, IL-10 displays bystander antagonism on unrelated autoreactive T dolls, allowing for reversal of disease involving multiple epitopes. Therefore, aggregated Ig-PLP1 likely brings together a peripheral T cell tolerance mechanism emanating from peptide presentation by APCs expressing suboptimal costimulatory molecules and IL-10 bystander suppression to drive a dual-modal T cell modulation system effective for reversal of autoimmunity involving several epitopes and diverse T cell specificities.