卡介苗辅助T淋巴细胞对耐药结核性脑膜炎的免疫治疗作用研究

耐药结核性脑膜炎(TBM)严重危害人类健康，免疫力下降是其重要病因，免疫治疗有很好前景。因存在血脑屏障，传统皮下注射卡介苗(BCG)难以激活脑脊液(CSF)T淋巴细胞，对TBM疗效欠佳。前期研究发现CSF内T淋巴细胞可吞噬结核分枝杆菌(Mtb)，且较未吞噬Mtb的TBM病人预后好。但人脑内T淋巴细胞对Mtb作用有限，若能通过脑内注射BCG增强T细胞作用效果，有望成为治疗TBM新的方法。进而预实验发现BCG可诱导人T淋巴细胞具有吞噬功能并提高吞噬率，同时自身细胞凋亡(坏死)降低并启动免疫炎症反应；吞噬BCG的T细胞还激活了细胞毒作用。我们推测BCG可能会诱导T细胞进一步吞噬杀伤耐药Mtb，以对耐药TBM发挥免疫治疗作用。对此我们将结合体外人T淋巴细胞、BCG、耐药Mtb共培养模型及耐药TBM小鼠模型探讨BCG辅助T淋巴细胞对耐药TBM的免疫治疗作用及机制，为治疗耐药TBM提供新思路。

Drug-resistant tuberculous meningitis (TBM) seriously harms human health. Immunity decline is an important cause, and immunotherapy has a good prospect. Due to the blood-brain barrier, traditional subcutaneous injection of BCG is difficult to activate cerebrospinal fluid (CSF) T lymphocytes, which is not effective for TBM. Previous studies have found that T lymphocytes in CSF can engulf Mycobacterium tuberculosis (Mtb) and have a better prognosis than TBM patients who do not engulf Mtb. However, T lymphocytes in human brain have a limited effect on Mtb. If T lymphocytes function can be enhanced by injecting BCG into the brain, it is expected to become a new method for treating TBM. Furthermore, pre-experiments found that BCG could induce human T lymphocytes to have phagocytosis function and increase phagocytosis rate. At the same time, auto-apoptosis (necrosis) was reduced and immune inflammatory response was initiated; T lymphocyte which engulfed BCG also activated cytotoxicity. We speculate that BCG may induce T lymphocyte to further phagocytose and kill drug-resistant Mtb, in order to exert immunotherapeutic effects on drug-resistant TBM. In this regard, we will explore the immunotherapy effect and mechanism of BCG and T lymphocytes on drug-resistant TBM in combination with human T lymphocytes, BCG, drug-resistant Mtb co-culture models and drug-resistant TBM mouse models in vitro, so as to offer new ideas for the treatment of drug resistant TBM.