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）疫苗在这些模型中治疗疾病的潜在作用。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： 具体目标1：建立外源性抗原诱导的膀胱炎症模型，以确定系统性Th 1和Th 2免疫极化在膀胱炎症发展中的作用。为了建立该模型，将从表达对卵清蛋白（OVA）抗原特异性的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成Th 1或Th 2亚群，并过继转移到遗传相容的小鼠中。将通过将OVA直接滴入膀胱来在受体小鼠中诱导膀胱炎。该模型特别适用于急性炎症的研究。 具体目标2。建立膀胱自身免疫性疾病模型，通过建立一种新的转基因小鼠品系，通过启动子特异性产生的尿钍表达OVA作为“自身”抗原，并确定Th免疫极化在这种疾病的发展中的作用。这种转基因小鼠品系（称为URO-OVA）将用含有膀胱特异性启动子和OVA基因的DNA进行遗传工程改造。通过极性OT-II Th细胞的过继转移，在这些URO-OVA小鼠中将产生自身免疫形式的膀胱炎。该模型特别适用于慢性炎症的研究。 具体目标3。探讨卡介苗对抗原性膀胱炎的治疗作用。将在外源性和内源性抗原诱导的膀胱炎模型中评价BCG对治疗Th 2极化膀胱炎（IC的假设类型）的作用。预计BCG将患病的Th 2免疫状态转变回有利的Th 1状态。这项研究的成功完成将建立Th 1和Th 2型膀胱炎的病理学和免疫学特征，揭示BCG治疗这种疾病的效果，并有助于IC和其他疼痛性膀胱疾病的预防和治疗策略的未来发展。

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.