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衰弱性膀胱疾病。最近的一项双盲试验，使用膀胱内卡介苗（BCG）治疗IC显示了60%的临床反应率，以一个单一的六周疗程的BCG。当对BCG有反应的受试者进行至少两年的随访时，89%的受试者继续具有极好的反应，尽管没有对其IC进行额外的治疗。这种治疗的持久性导致人们推测膀胱内BCG可能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受试者尿液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应答。此外，在特应性皮炎（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病因学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BCG是有效的，通过将细胞因子环境转化为Th-1，导致修复条件和长期的临床反应。具体而言，本研究将：1）确定符合间质性膀胱炎的NIDDK标准的受试者和健康对照受试者的尿细胞因子谱; 2）以盲法确定在6周一次滴注卡介苗（BCG）或安慰剂期间以及在6个月随访期间以规则间隔的尿细胞因子的变化; 3）将细胞因子的变化与临床应答相关联;和4）确定某种细胞因子谱细胞因子谱是否可以预测对膀胱内BCG治疗的临床反应。这项研究将涉及我们目前的膀胱内BCG治疗IC的临床试验中招募的受试者。将通过酶联免疫吸附试验测定细胞因子水平，一式三份，并根据尿肌酸进行标准化。将通过非参数方法分析研究结果。此外，将完成接收操作特征分析，以确定用于预测治疗临床应答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。通过将膀胱内BCG治疗之前、期间和之后的细胞因子水平的变化相关联，我们将建立这些细胞因子在IC中的作用，并使用变化模式作为预测受试者对治疗的反应的手段。此外，这项研究将开辟一条新的研究途径，具有开发更有效、毒性更低的IC治疗方法的长期潜力。

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.