Molecular analysis of the abnormal T cell function as a pathogenesis of autoimmune diseases

T 细胞功能异常作为自身免疫性疾病发病机制的分子分析

• 批准号: 03807038
• 负责人: HIROHATA Shunsei
• 金额: $ 1.22万
• 依托单位: Teikyo University School of Medicine (1992)The University of Tokyo (1991)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03807038/
• 关键词: B lymphocyte; suppressor T cells; cell-to-cell contact; Anti-CD3 antibody; Ig production; DNA polymerase; ICAM-1; LFA-1; サプレッサ-T細胞; ICAMー1; LFAー1

To clarify the mechanism of abnormal T cell functions in various autoimmune diseases, we have explored the nature of human suppressor T cells in several aspects. We have utilized the culture system with immobilized mAb to CD3 molecular complex, in which B cells are very potently activated through direct interactions with stimulated T cells. We have obtained the following results. First, we have demonstrated that the suppression of B cell differentiation by human suppressor T cells requires the direct interactions between ICM-1 on activated B cells and LFA-1 on suppressor T cells. Second, we have revealed that the expression of DNA polymerase alpha in B cells is inhibited by human suppressor T cells in a reversible fashion.Finally, we have disclosed that anti-CD3 activated CD4+ T cells as well as CD8+ T cells irrespective of their expression of CD45RA molecule are able to stimulate resting B cells to express IL-2 receptor (CD25), at the same time when they suppress the maturation of previously activated B cells, indicating that human activated T cells can simultaneously provide help as well as suppression irrespective of their phenotypes. It is rather suggested that the state of activation of B cells might be important in determining of functions of the activated T cells.All of these results have added novel findings to the body of knowledge about human suppressor T cells, and thus may contribute to the investigation into the pathogenesis of systemic lupus erythematous, in which the deficient suppressor T cell function plays a critical role.

为了阐明各种自身免疫性疾病中T细胞功能异常的机制，我们从几个方面探讨了人类抑制性T细胞的性质。我们利用了CD3分子复合物的固定化mAb培养系统，在该系统中，B细胞通过与刺激的T细胞直接作用而被非常有效地激活。我们取得了以下成果。首先，我们已经证明，人类抑制性T细胞对B细胞分化的抑制需要激活B细胞上的ICM-1和抑制性T细胞上的LFA-1之间的直接相互作用。其次，我们揭示了人类抑制性T细胞以可逆的方式抑制B细胞中DNA聚合酶α的表达。最后，我们揭示了抗CD3激活的CD4+T细胞以及CD8+T细胞无论其CD45RA分子的表达如何，在抑制先前激活的B细胞成熟的同时，能够刺激静止的B细胞表达IL-2受体(CD25)，这表明人类激活的T细胞无论其表型如何，都可以同时提供帮助和抑制。这些结果为人类抑制性T细胞的研究增添了新的发现，从而有助于研究系统性红斑狼疮的发病机制，而抑制性T细胞功能的缺陷在其中起着关键作用。

项目成果

Oka H,Hirohata S,Inoue T,Ito K.: "Effects of interferonーα on human B cell responsiveness:Biphasic effects in cultures stimulated with Staphylococcus aureus." Cell Immunol. 139. 478-492 (1992)

Oka H、Hirohata S、Inoue T、Ito K.：“干扰素-α 对人类 B 细胞反应性的影响：金黄色葡萄球菌刺激的培养物中的双相效应”139. 478-492 (1992)。

Oka H,Hirohata S,Inoue T,Ito K.: "Effect of interferon-α on human B cell responsiveness: Biphasic effects in cultures stimulated with Staphylococcus aureus." Cell.Immunol.139. 478-492 (1992)

Oka H、Hirohata S、Inoue T、Ito K.：“干扰素-α 对人类 B 细胞反应性的影响：金黄色葡萄球菌刺激的培养物中的双相效应。Cell.Immunol.139（1992）”

Shinohara S,Hirohata S,Inoue T,Ito K.: "Phenotypic analysis of peripheral blood monocytes isolated from patients with rheumatoid arthritis." J Rheumatol. (1992)

Shinohara S、Hirohata S、Inoue T、Ito K.：“从类风湿性关节炎患者中分离的外周血单核细胞的表型分析。”

Oka H,Hirohata S.: "Regulation of human B cell responsiveness by interferon-α: Interferon-α mediated suppression of B cell function is reversed through direct interactions between monocytes and B cells." Cell.Immunol.146. 238-248 (1993)

Oka H，Hirohata S.：“干扰素-α 调节人类 B 细胞反应性：干扰素-α 介导的 B 细胞功能抑制可通过单核细胞和 B 细胞之间的直接相互作用逆转。”146- 248（1993）

Hirohata S.Oka H,Mizushima Y.: "Streptococcal related antigens stimulate production of IL6 and interferonーγ by T cells from patients with Behcet's disease." Cell Immunol. (1992)

Hirohata S.Oka H，Mizushima Y.：“链球菌相关抗原刺激白塞病患者 T 细胞产生 IL6 和干扰素-γ”（1992 年）。