Analysis of Txk functions in the development of Th1 cells and its application for treatment of autoimmune and allergic diseases

Txk在Th1细胞发育中的功能分析及其在自身免疫和过敏性疾病治疗中的应用

• 批准号: 14370166
• 负责人: SUZUKI Noboru
• 金额: $ 9.09万
• 依托单位: St. Marianna University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370166/
• 关键词: Txk; IFN-gamma; Th1 cell; Transcriptions; IgE; 花粉症; プロモーター領域

T helper type 1 (Th1) and Th2 cells, resulting from antigenic stimulation in the presence of interleukin (IL)-12 and IL-4, respectively, are implicated in the pathology of diseases including allergic and autoimmune diseases.Txk/Rlk is a member of Tec family tyrosine kinases. We have reported that Txk acts as a Th1 cell specific transcription factor in the T lymphocytes. We found that Txk expression was affected positively by IL-12, IL-18 and IFN-g and negatively by IL-4 and IL-13.We next studied whether administration of txk expression plasmid induced expression of Txk in their spleen cells. The spleen cells from the mice administered txk expression plasmid produced more IFN-gamma as compared with those from mice administered control plasmid in an antigen specific manner. IL-2 and IL-4 secretion of the spleen cells were comparable between the two mouse groups. Txk administration did not reduce serum IgG concentration.However, it markedly reduced serum total IgE level and an IgG1/IfG2a ration, reflection of Th1/Th2 balance. Furthermore, txk administration reduced the antigen specific IgE levels in sera of the mice, which was used for immunizing mice. Thus, Txk enhances IFN-g secretion and thus modulates Th1/Th2 cytokine balance, leading to reduction of serum IgE in an antigen specific manner in vivo.

Th 1和Th 2细胞分别在白细胞介素（IL）-12和IL-4的存在下由抗原刺激产生，参与包括过敏性和自身免疫性疾病在内的疾病的病理学过程。我们已经报道Txk在T淋巴细胞中作为Th 1细胞特异性转录因子。结果发现，IL-12、IL-18和IFN-γ对Txk表达有正性影响，而IL-4和IL-13对Txk表达有负性影响。与来自以抗原特异性方式施用对照质粒的小鼠的脾细胞相比，来自施用txk表达质粒的小鼠的脾细胞产生更多的IFN-γ。两组小鼠脾细胞的IL-2和IL-4分泌相当。Txk治疗不降低血清IgG浓度，但显著降低血清总IgE水平和IgG 1/IfG 2a比值，反映Th 1/Th 2平衡。此外，TXK给药降低了用于免疫小鼠的小鼠血清中的抗原特异性IgE水平。因此，Txk增强IFN-g分泌，从而调节Th 1/Th 2细胞因子平衡，导致体内以抗原特异性方式降低血清IgE。

项目成果

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Mihara S：“分子拟态和异常自身抗原表达的结合对于 SLE 患者抗 Fas 配体和自身抗体的开发非常重要”Clin Exp Immuol。

Mihara S, Suzuki N, Takeba Y, Soejima K, Yamamoto Y: "Combination of molecular mimicry and aberrant autoantigen expression is important for development of anti-Fas ligand autoantibodies in patients with SLE"Clin Exp Immunol. 129. 359-369 (2002)

Mihara S、Suzuki N、Takeba Y、Soejima K、Yamamoto Y：“分子拟态和异常自身抗原表达的结合对于 SLE 患者抗 Fas 配体自身抗体的开发非常重要”Clin Exp Immunol。

Nagafuchi H: "Recombination activating genes (RAG) induce secondary Ig gene rearrangement in and subsequent apoptosis of human peripheral blood circulating B lymphocytes"Clin Exp Immunol. 136. 76-84 (2004)

Nagafuchi H：“重组激活基因 (RAG) 诱导人外周血循环 B 淋巴细胞中的二次 Ig 基因重排以及随后的细胞凋亡”Clin Exp Immunol。

Matsusita S: "Evidence for immunosuppressive effects of human sermenogelin, a major protein of seminal plasma."St.Marianna Med. (in press). (2004)

Matsusita S：“人精蛋白（精浆的主要蛋白质）免疫抑制作用的证据。”St.Marianna Med。

Miyagi T, Takeno M, Nagafuchi H, Takahashi M, Suzuki N: "Flk1 positive cells derived from mouse embryonic stem (ES) cells reconstitutes hematopoiesis in vivo in SCID mice"Exp Hematol. 30(12). 1444-1453 (2002)

Miyagi T、Takeno M、Nagafuchi H、Takahashi M、Suzuki N：“源自小鼠胚胎干 (ES) 细胞的 Flk1 阳性细胞在 SCID 小鼠体内重建造血功能”Exp Hematol。