Selective Suppression of Pathogenic T Cell Responses Using Dendritic Cells

使用树突状细胞选择性抑制致病性 T 细胞反应

• 批准号: 09307011
• 负责人: IKEDA Yasuo
• 金额: $ 18.5万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09307011/
• 关键词: dendritic cell; T cell; autoimmune disease; HLA; immunotherapy; immune thrombocytopenic purpura; scleroderma; antiphospholipid syndrome; 自己免疫性血小板減少症; 抗腫瘍免疫; 造血器腫瘍

Dendritic cells (DC) are Antigen-presenting cells that are essential for initiation of T cell-dependent immunity, but distinct DC subsets are known to direct different classes of immune responses. Lymphoid DC precursors (pDC2) or plasmacytoid DC were recently identified as a human DC subset producing type I interferon and skewing Th2 responses. Here, we demonstrate that pDC2 isolated from human peripheral blood have a capacity to induce an anergic state in antigen-specific CD4^+ T cell lines. Tetanus toxoid (TT)-specific T cells incubated with TT-pulsed autologous pDC2 failed to proliferate in secondary cultures with optimal antigenic stimulation. T cell anergy induction required T cell receptor engagement with antigen/major histocompatibility complex presented on pDC2. The pDC2-induced unresponsiveness was completely or partially reversible in the presence of high-dose IL-2 in the secondary cultures. Autoreactive CD4^+ T cell clones specific for topoisomerase I derived from a patient with scleroderma were rendered anergic after coculture with topoisomerase I-pulsed autologous pDC2, resulting in failure to proliferate or provide help to B cells. These results suggest that pDC2 are involved in maintenance of peripheral T cell tolerance and have potential for use in the suppression of pathogenic T cell responses in autoimmune diseases and organ transplantation.

树突状细胞（DC）是抗原呈递细胞，对于启动T细胞依赖性免疫至关重要，但已知不同的DC亚群可以指导不同类别的免疫反应。最近将淋巴样DC前体（PDC2）或浆细胞类动物DC鉴定为人类DC子集产生I型干扰素和偏斜Th2响应。在这里，我们证明了从人外周血分离的PDC2具有在抗原特异性CD4^+ T细胞系中诱导厌食状态的能力。与TT脉冲自体PDC2孵育的破伤风毒素（TT）特异性T细胞未能在具有最佳抗原刺激的二次培养物中增殖。 T细胞消极诱导需要在PDC2上介绍的抗原/主要组织相容性复合物的T细胞受体接合。在二级培养物中，PDC2诱导的非反应性是完全或部分可逆的。与拓铁皮病患者衍生的拓扑异构酶I特异性的自动反应性CD4^+ T细胞克隆在与拓扑异构酶I脉冲型自体PDC2的共培养后，导致厌食症，导致未能增殖或为B细胞提供帮助。这些结果表明，PDC2参与维持周围T细胞的耐受性，并具有在自身免疫性疾病和器官移植中抑制致病性T细胞反应的潜力。

项目成果

Kuwana M, Ikeda Y, et al.: "Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura : role in production of anti-platelet autoantibody"Journal of Clinical Investigation. 102-7. 1393-1402 (1998)

Kuwana M、Ikeda Y 等人：“免疫性血小板减少性紫癜中血小板 GPIIb-IIIa 的自身反应性 T 细胞：在抗血小板自身抗体产生中的作用”临床研究杂志。

Kaburaki J,Ikeda Y,et al.: "Anti-cardiolipin-β2-GPI complex antibodies in idiopathic thrombocytopenic purpura" Intern Med. 37・9. 796 (1998)

Kaburaki J、Ikeda Y 等：“特发性血小板减少性紫癜中的抗心磷脂-β2-GPI 复合物抗体” Intern Med 37·9 (1998)。

Hattori N,Ikeda Y,et al.: "T cells that are autoreactive to β2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals"Arthritis and Rheumatism. 43・1. 65-75 (2000)

Hattori N、Ikeda Y 等人：“抗磷脂综合征患者和健康个体中对 β2-糖蛋白 I 具有自身反应的 T 细胞”关节炎和风湿病 43・1 (2000)。

桑名正隆、池田康夫: "ITPにおける自己抗体産生機序"日本内科学会雑誌. 88・12. 2493-2498 (1999)

Masataka Kuwana，Yasuo Ikeda：“ITP 中的自身抗体产生机制”日本内科学会杂志 88・12 2493-2498（1999）。

桑名正隆,池山康夫: "ITPにおける自己抗体産生機序"日本内科学会雑誌. 88・12. 2493-2498 (1999)

Masataka Kuwana，Yasuo Ikeyama：“ITP 中的自身抗体产生机制”日本内科学会杂志 88・12 2493-2498（1999）。