IMMUNE MEDIATORS IN INTERSTITIAL CYSTITIS

间质性膀胱炎（IC）是一种病因不明且无法治愈的严重膀胱衰弱性疾病。最近一项使用膀胱内卡介苗治疗IC的双盲试验显示，单次6周卡介苗疗程的临床缓解率为60%。当对卡介苗有反应的受试者进行至少两年的随访时，尽管没有对其IC进行额外治疗，89%的患者仍有良好的反应。这种治疗的持久性使人们推测膀胱内卡介苗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辅助t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白细胞介素-6和白细胞介素-2抑制剂水平升高，提示Th-2反应。此外，在特应性皮炎（一种Th-2介导的疾病）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，而膀胱内卡介苗通过将细胞因子环境转化为Th-1谱而有效，从而导致修复性条件和长期临床反应。具体而言，本研究将：1)确定符合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)在6个月的随访期间，以盲法测定每6周注射卡介苗（BCG）或安慰剂期间尿液细胞因子的变化；3)将细胞因子的变化与临床反应联系起来；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反应。本研究将纳入我们目前膀胱内卡介苗治疗IC临床试验的受试者。细胞因子水平将通过酶联免疫吸附法测定，并根据尿肌酸标准化。研究结果将采用非参数方法进行分析。此外，将完成接收操作特征分析，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。通过将细胞因子水平在膀胱内卡介苗治疗之前、期间和之后的变化联系起来，我们将确定这些细胞因子在IC中的作用，并使用变化模式作为预测受试者对治疗反应的手段。此外，这项研究将为开发更有效、毒性更小的IC治疗方法开辟一条新的研究途径，具有特定的长期潜力。

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.