Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease
Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease
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DOI：
10.4049/jimmunol.173.3.2118
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Yamamoto, K
中科院分区：
文献类型：
--
作者：
Fujio, K;Okamoto, A;Yamamoto, K
系统性自身免疫性疾病的机制尚不清楚，现有的治疗方法往往导致免疫抑制。我们在此描述了一种基于自身抗原呈递部位的自身抗原特异性免疫治疗的新模式。核小体是一种特性良好的自身抗原。我们在（NZB x NZW）F-1 （NZB/W F-1）狼疮易感小鼠中发现了核小体特异性T细胞的相对脾定位刺激能力。来自NZB/W F-1小鼠的脾树突状细胞自发刺激核小体特异性T细胞的程度远高于来自正常小鼠的树突状细胞和来自NZB/W F-1小鼠淋巴结的树突状细胞。这导致了一种利用自身抗原特异性T细胞局部递送治疗分子的策略。通过三重基因转移（tcr - α、tcr - β和CTLA4Ig）工程化的核小体特异性调节性T细胞在脾脏中积累并抑制相关病原性自身抗体的产生。肾炎得到了明显的抑制。损害T细胞依赖的体液免疫反应。因此，通过多基因转移改造的自身抗原特异性调节性T细胞是治疗自身免疫性疾病的一种很有前途的策略。
The mechanisms of systemic autoimmune disease are poorly understood and available therapies often lead to immunosuppressive conditions. We describe here a new model of autoantigen-specific immunotherapy based on the sites of autoantigen presentation in systemic autoimmune disease. Nucleosomes are one of the well-characterized autoantigens. We found relative splenic localization of the stimulative capacity for nucleosome-specific T cells in (NZB x NZW)F-1 (NZB/W F-1) lupus-prone mice. Splenic dendritic cells (DCs) from NZB/W F-1 mice spontaneously stimulate nucleosome-specific T cells to a much greater degree than both DCs from normal mice and DCs from the lymph nodes of NZB/W F-1 mice. This leads to a strategy for the local delivery of therapeutic molecules using autoantigen-specific T cells. Nucleosome-specific regulatory T cells engineered by triple gene transfer (TCR-alpha, TCR-beta, and CTLA4Ig) accumulated in the spleen and suppressed the related pathogenic autoantibody production. Nephritis was drastically suppressed without. impairing the T cell-dependent humoral immune responses. Thus, autoantigen-specific regulatory T cells engineered by multiple gene transfer is a promising strategy for treating autoimmune diseases.