IMMUNE MEDIATORS IN INTERSTITIAL CYSTITIS

间质性膀胱炎是一种病因不明、无法治愈的严重衰弱性膀胱疾病。最近一项使用卡介苗(BCG)膀胱内注射治疗IC的双盲试验显示，单次卡介苗6周疗程的临床有效率为60%。当对卡介苗有反应的受试者被跟踪至少两年时，89%的受试者继续有良好的反应，尽管他们的IC没有额外的治疗。这种治疗的持久性导致人们推测BCG膀胱内注射治疗间质性膀胱炎的机制。有证据表明，间质性膀胱炎可能是由膀胱内的T辅助细胞2型(Th-2)反应介导的。IC患者尿液中的细胞因子分析显示IL-6和IL-2抑制物水平升高，提示存在Th-2反应。此外，在特应性皮炎和间质性膀胱炎中也发现了类似的自身抗体。然而，免疫系统在IC病因中的作用仍然存在争议。我们假设间质性膀胱炎是一种Th-2介导的疾病，导致慢性炎症，膀胱内注射卡介苗通过将细胞因子环境转换为Th-1而有效，导致修复条件和长期临床反应。具体地说，这项研究将：1)测定符合NIDDK间质性膀胱炎标准的受试者和健康对照受试者的尿液细胞因子谱；2)盲法测定每周6次卡介苗(BCG)或安慰剂滴注期间尿液细胞因子的变化，并在6个月的随访中每隔一段时间定期测定尿液细胞因子的变化；3)将细胞因子的变化与临床反应相关联；4)确定某种细胞因子谱细胞因子谱是否可以预测膀胱内卡介苗治疗的临床疗效。这项研究将纳入我们目前膀胱内卡介苗治疗IC的临床试验的受试者。细胞因子水平将通过酶联免疫吸附试验测定一式三份，并与尿肌酸进行标准化。研究结果将采用非参数方法进行分析。此外，还将完成接收操作特性分析，以确定预测临床治疗反应的关键细胞因子水平。总之，本研究将确定IC受试者和健康受试者的细胞因子谱。通过比较卡介苗治疗前、中、后细胞因子水平的变化，我们将确定这些细胞因子在IC中的作用，并将其作为预测受试者治疗反应的一种手段。此外，这项研究将为开发更有效、毒性更低的IC治疗方法开辟一条具有特定长期潜力的新研究途径。

Interstitial cystitis (IC) is a severe debilitating bladder disease of unknown etiology and no cure. A recent double-blind trial using intravesical Bacillus Calmette Guerin (BCG) to treat IC demonstrated a 60% clinical response rate to a single six week course of BCG. When subjects who responded to BCG were followed for a minimum of two years, 89% continued to have an excellent response, despite no additional treatment of their IC. The durability of this treatment leads one to speculate on the mechanism in which intravesical BCG may treat interstitial cystitis. There is evidence that interstitial cystitis may be mediated by a T-Helper Cell type-2 (Th-2) response within the bladder. Cytokine analysis from the urine of IC subjects showed elevated levels of Interleukin-6 and inhibitors of interleukin-2, suggesting a Th-2 response. In addition, similar autoantibodies have been identified in both atopic dermatitis, a Th-2 mediated disease, and interstitial cystitis. However, the role of the immune system in the etiology of IC remains controversial. We hypothesize that interstitial cystitis is a Th-2 mediated disease leading to chronic inflammation and that intravesical BCG is effective by converting the cytokine milieu to a Th-1 profile, leading to reparative conditions and long-term clinical response. Specifically, this study will: 1) determine the urine cytokine profiles in subjects meeting the NIDDK criteria for interstitial cystitis and in health control subjects; 2) determine in a blinded fashion the changes in urinary cytokines during six weekly instillations of either bacillus Calmette-Guerin (BCG) or placebo and at regular intervals during a 6 month follow-up; 3) correlate changes in cytokines with clinical response; and 4) determine whether a certain cytokine profile cytokine profile can predict clinical response to intravesical BCG therapy. This study will involve subjects enrolled in our present clinical trial of intravesical BCG therapy for IC. Cytokine levels will be determined in triplicate by enzyme-linked immunosorbant assays and normalized against urine creatine. Study results will be analyzed by non-parametric methods. In addition, a receiving operating characteristic analysis will be completed to determine the critical cytokines levels for predicting clinical response to treatment. In summary, this study will determine the cytokine profile in IC subjects and healthy subjects. By correlating the changes in cytokine levels before, during and following intravesical BCG therapy, we will establish the role of these cytokines in IC and use the pattern of change as a means to predict subject response to therapy. Additionally, this study will open a new avenue of research with specific long-term potential for the development of more effective, less toxic treatments of IC.