BCG in Endogeneous and Exogenous Antigen-Induced T Cell

内源性和外源性抗原诱导 T 细胞中的卡介苗

• 批准号: 6803502
• 负责人: YI LUO
• 金额: $ 14.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803502
• 关键词: Bacillus Calmette Guerin vaccine; Mycobacterium bovis; autoantigens; autoimmune disorder; biotechnology; biotherapeutic agent; disease /disorder model; genetically modified animals; helper T lymphocyte; immunomodulators; immunopathology; immunotherapy; inflammation; interstitial cystitis; laboratory mouse; neurogenic urinary bladder disorder; nonhuman therapy evaluation; ovalbumin; transfection; urinary bladder epithelium; urinary tract disorder chemotherapy; urinary tract pharmacology

DESCRIPTION (provided by applicant): The purpose of this project is to create antigen-induced T helper (Th) polarized bladder inflammation models to mimic the postulated pathogenesis of interstitial cystitis (IC) and investigate the potential effect of the Bacillus Calmette-Guerin (BCG) vaccine on treating the disease in these models. The long-term goal is to develop effective treatment strategies to combat IC. Towards achieving these goals, three specific aims will be undertaken: Specific Aim 1: To create an exogenous antigen-induced bladder inflammation model to determine the role of systemic Thl and Th2 immune polarization in the development of bladder inflammation. To create this model, T helper cells will be isolated from transgenic mice (termed OT-II) that express Th cells specific for the ovalbumin (OVA) antigen. These Th cells will be differentiated in the laboratory into Thl or Th2 subsets, and adoptively transferred into genetically compatible mice. Cystitis will be induced in the recipient mice by instilling OVA directly into the bladder. This model will particularly lend itself to studies on acute inflammation. Specific Aim 2. To establish a bladder autoimmune disease model by creating a novel transgenic mouse strain that expresses OVA as a "self" antigen via promoter-specific production by the urothelium and to determine the role of the Th immune polarization in the development of this disease. This transgenic mouse strain (termed URO-OVA) will be genetically engineered with DNA containing a bladder-specific promoter and the gene for OVA. An autoimmune form of cystitis will be developed in these URO-OVA mice by adoptive transfer of polarized OT-II Th cells. This model particularly lends itself to studies on chronic inflammation. Specific Aim 3. To assess the therapeutic effect of BCG in antigen-induced bladder inflammation. BCG will be evaluated for its effect on treating Th2 polarized cystitis (the hypothesized type responsible for IC) in both exogenous and endogenous antigen-induced cystitis models. BCG is predicted to shift the diseased Th2 immune state back to a favorable Th1 state. Successful completion of this study will establish the pathological and immunological characteristics for both Th1 and Th2 type cystitis, shed light on BCG's effect on treating this disease, and aid in the future development of prevention and treatment strategies for IC and other painful bladder conditions.

描述（由申请人提供）： 该项目的目的是创建抗原诱导 T 辅助细胞 (Th) 极化膀胱炎症模型，以模拟间质性膀胱炎 (IC) 的假设发病机制，并研究卡介苗 (BCG) 疫苗治疗该疾病的潜在效果在这些模型中。长期目标是开发有效的治疗策略来对抗 IC。为了实现这些目标，将实现三个具体目标： 具体目标1：建立外源抗原诱导的膀胱炎症模型，以确定全身Th1和Th2免疫极化在膀胱炎症发展中的作用。为了创建该模型，将从转基因小鼠（称为 OT-II）中分离出 T 辅助细胞，这些小鼠表达对卵清蛋白 (OVA) 抗原具有特异性的 Th 细胞。这些 Th 细胞将在实验室中分化为 Th1 或 Th2 亚群，并过继转移至遗传相容的小鼠体内。通过将 OVA 直接滴注到膀胱中，在受体小鼠中诱发膀胱炎。该模型特别适合急性炎症的研究。 具体目标 2. 通过创建一种新的转基因小鼠品系来建立膀胱自身免疫性疾病模型，该品系通过尿路上皮的启动子特异性产生来表达 OVA 作为“自身”抗原，并确定 Th 免疫极化在该疾病发展中的作用疾病。这种转基因小鼠品系（称为 URO-OVA）将采用含有膀胱特异性启动子和 OVA 基因的 DNA 进行基因工程改造。通过极化 OT-II Th 细胞的过继转移，这些 URO-OVA 小鼠将出现自身免疫性膀胱炎。该模型特别适合慢性炎症的研究。 具体目标 3. 评估卡介苗对抗原诱导的膀胱炎症的治疗效果。将在外源性和内源性抗原诱导的膀胱炎模型中评估卡介苗对治疗 Th2 极化膀胱炎（推测的 IC 类型）的效果。预计卡介苗可以将患病的 Th2 免疫状态转变回有利的 Th1 状态。这项研究的成功完成将确定 Th1 和 Th2 型膀胱炎的病理学和免疫学特征，阐明卡介苗治疗该疾病的效果，并有助于未来制定 IC 和其他膀胱疼痛性疾病的预防和治疗策略。