Oral or nasal antigen induces regulatory T cells that suppress arthritis and proliferation of arthritogenic T cells in joint draining lymph nodes
Oral or nasal antigen induces regulatory T cells that suppress arthritis and proliferation of arthritogenic T cells in joint draining lymph nodes
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DOI：
10.4049/jimmunol.181.2.899
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发表时间：
2008-07-15
影响因子：
4.4
通讯作者：
van Eden, Willem
中科院分区：
文献类型：
--
作者：
Broere, Femke;Wieten, Lotte;van Eden, Willem
作为自身免疫性疾病的治疗方法，粘膜耐受的传播仍然是一个难以实现的目标，因此需要进一步的机制研究来开发潜在的临床方案以诱导粘膜调节性T细胞（Tr细胞）。在这项研究中，我们解决了口服或鼻腔蛋白多糖诱导功能性Tr细胞在软骨蛋白多糖诱导的慢性关节炎模型。在诱发疾病前经鼻和经口应用人蛋白聚糖均能抑制关节炎的严重程度和发病率。耐受小鼠的爪子引流淋巴结中产生IL-10的CD 4（+）细胞数量增加。此外，CD 4（+）脾细胞显示与Tr细胞相关的分子（如IL-10、Foxp 3和TGF-β）表达增强。将来自粘膜耐受供体的CD 4（+）脾细胞转移到蛋白聚糖免疫小鼠中，可消除关节炎并降低体液应答，表明Tr细胞具有抑制已诱导的免疫应答的能力。Tr细胞在转移后被激活，因为与来自非耐受供体的活化T细胞相比，在关节引流淋巴结中观察到增强的增殖。在与幼稚蛋白聚糖特异性T细胞共转移后，粘膜诱导的Tr细胞在体内抑制这些致关节炎T细胞的增殖。在这里，我们表明，口服和鼻腔Ag应用诱导Tr细胞，这对已经建立的致病性B和T细胞反应有直接的抑制作用。
The propagation of mucosal tolerance as a therapeutic approach in autoimmune diseases remains a difficult goal to achieve, and therefore further mechanistic studies are necessary to develop potential clinical protocols to induce mucosal regulatory T cells (Tr cells). In this study we addressed whether oral or nasal proteoglycan induced functional Tr cells in the cartilage proteoglycan-induced chronic arthritis model. Both nasal and oral application of human proteoglycan before induction of disease suppressed arthritis severity and incidence. Tolerized mice showed enhanced numbers of IL-10 producing CD4(+) cells in the paw-draining lymph nodes. Furthermore, CD4(+) spleen cells displayed enhanced expression of molecules associated with Tr cells, such as IL-10, Foxp3, and TGF-beta. Transfer of CD4(+) spleen cells from mucosally tolerized donors into proteoglycan-immunized mice abolished arthritis and reduced humoral responses, indicative of Tr cells with the capacity to inhibit already induced immune responses. Tr cells were activated upon transfer, because enhanced proliferation was observed in the joint draining lymph nodes compared with activated T cells from nontolerized donors. Upon cotransfer with naive proteoglycan-specific T cells, mucosally induced Tr cells inhibited proliferation of these arthritogenic T cells in vivo. Herein we show that both oral and nasal Ag application induced Tr cells, which had a direct inhibitory effect on already established pathogenic B and T cell responses.