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Characterization of T cell receptor (TCR) of neurological autoimmune disease-inducing T cells and TCR-based immunotherapy with DNA vaccines

诱导神经系统自身免疫性疾病的 T 细胞的 T 细胞受体 (TCR) 的表征以及基于 TCR 的 DNA 疫苗免疫治疗

基本信息

批准号：
10357005
负责人：
MATSUMOTO Yoh
金额：
$ 20.99万
依托单位：
Tokyo metropolitan Institute for Neuroscience (1999-2000)Tokyo Metropolitan Institute for Neuroscience (1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10357005/
关键词：
Central nervous system Autoimmune disease T cell receptor CDR3 spectratyping DNA avaccine

项目摘要

In this study, we have modified and applied CDR3 spectratyping analysis which is a sensitive method to detect T cell clonal expansion to identify T cells bearing autoimmune disease-associated T cells (TCR). Based on the results obtained by the analysis, we have made DNA vaccines i.e. expression vectors encoding the Vbeta chain of TCR of encepahlotogenic T cells, and tried to protect animals immunized with neuroantigen plus complete Freund adjuvant from the development of experimental autoimmune encephalomyelitis(EAE). The basic principle of DNA vaccination therapy is as follows. When DNA vaccines are injected in animals, TCR genes are transcribed and translated into TCR oriteubs. Then, these proteins overexpressed in vaccinated animals induce anti-TCR antibodies and/or regulatory T cells, which in tern inhibit the proliferation of encephalitogenic T cells bearing the same TCR.The TCR duagbisus abd DNA vaccination therapy established in animal models will provide useful information to t … More he development of TCR analysis and TCR-based immunotherapy in human diseases in the near future.In EAE induced in Lewiw rats, we found that 1)Vβ8.2 clonal expansion was observed in T cells infiltrating the central nevous system(CNS), 2)this finding was observed not only in the CNS, but also in peripheral blood lymphocyts, enabling the diagnosis of the disease satus using the peripheral blood, and that 3)when the major encephalitogenic T cells bearing Vβ8.2 were depleted with the corresponding antibody, second encephalitogenic T cells bearing Vβ10 were newly activated. These findings suggest that TCR-based immunotherapy should be directed at these T cells simultaneously to obtain sufficient desease suppression.In our recent studies, we identified autoimmune cardititis-inducing T cells that had been not known by CDR3 spectratyping and seceeded in preventing the disease by injection of the corresponding TCR DNA vaccine(J.Immunol., 2000). However, the effects of vaccines on EAE suppression is not sufficient. By improving the vaccine constructs and determining the most effective protocols for vaccine administration, reliable DNA vaccination should be established. Our final goal is to develop TCR-based immunotherapy for human neurological autoimmune diseases. Less

在这项研究中，我们已经修改和应用CDR 3光谱分析，这是一种敏感的方法来检测T细胞克隆扩增，以确定T细胞携带自身免疫性疾病相关的T细胞（TCR）。基于上述分析结果，我们制备了编码致脑炎T细胞TCR V β链的DNA疫苗，并试图保护用神经抗原加完全弗氏佐剂免疫的动物免受实验性自身免疫性脑脊髓炎（EAE）的发展。DNA疫苗治疗的基本原理如下。当将DNA疫苗注射到动物体内时，TCR基因被转录并翻译成TCR位点。这些蛋白在免疫动物体内过表达，诱导产生抗TCR抗体和/或调节性T细胞，从而抑制携带相同TCR的致脑炎性T细胞的增殖。 ...更多信息在Lewiw大鼠EAE模型中，我们发现：1）在中枢神经系统（CNS）浸润的T细胞中观察到Vβ8.2克隆性扩增; 2）不仅在CNS中观察到，而且在外周血淋巴细胞中也观察到这一发现，这使得利用外周血诊断疾病状态成为可能，3）当携带Vβ8.2的主要致脑炎性T细胞被相应的抗体去除后，携带Vβ10的第二致脑炎性T细胞被新激活。在我们最近的研究中，我们鉴定了自身免疫性心肌炎诱导T细胞，这些细胞通过注射相应的TCR DNA疫苗在预防疾病中的CDR 3谱和分泌是未知的（J.Immunol.，2000）。然而，疫苗对EAE的抑制作用是不够的。通过改进疫苗构建体和确定最有效的疫苗施用方案，应该建立可靠的DNA疫苗接种。我们的最终目标是开发针对人类神经系统自身免疫性疾病的基于TCR的免疫疗法。少