BCG in Endogeneous and Exogenous Antigen-Induced T Cell

描述(由申请人提供)： 本项目的目的是建立抗原诱导的辅助性T细胞(Th)极化膀胱炎模型，模拟间质性膀胱炎(IC)的发病机制，并探讨卡介苗(BCG)对该模型的潜在治疗作用。长期目标是开发有效的治疗策略来对抗IC。为实现这些目标，将实现三个具体目标： 具体目的1：建立外源性抗原诱导的膀胱炎模型，探讨系统性Th1和Th2免疫极化在膀胱炎发生发展中的作用。为了建立这个模型，将从表达卵清蛋白(OVA)抗原特异性Th细胞的转基因小鼠(称为OT-II)中分离T辅助细胞。这些Th细胞将在实验室中分化为Th1或Th2亚群，并过继转移到基因相容的小鼠体内。通过将OVA直接注入到膀胱中，将在受体小鼠中诱导膀胱炎。这一模型尤其适用于急性炎症的研究。 目的2.建立膀胱自身免疫性疾病模型，建立一种新型转基因小鼠株系，通过尿路上皮基因启动子特异性产生表达OVA的自身抗原，并确定Th免疫极化在该疾病发展中的作用。这种转基因小鼠品系(被称为Uro-OVA)将被用含有膀胱特异启动子和OVA基因的DNA进行基因工程。通过过继转移极化的OT-II Th细胞，将在这些Uro-OVA小鼠身上形成一种自身免疫性膀胱炎。这个模型特别适合于慢性炎症的研究。 具体目的3.评价卡介苗对抗原性膀胱炎的治疗作用。在外源性和内源性抗原诱导的膀胱炎模型中，BCG将评估其治疗Th2极化膀胱炎(假想的导致IC的类型)的效果。据预测，卡介苗将使患病的Th2免疫状态恢复到良好的Th1状态。这项研究的成功完成将确立Th1型和Th2型膀胱炎的病理和免疫学特征，阐明卡介苗治疗这种疾病的效果，并有助于未来制定预防和治疗IC和其他疼痛膀胱疾病的策略。

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.