IMMUNE MEDIATORS IN INTERSTITIAL CYSTITIS

间质性膀胱炎中的免疫介质

• 批准号: 6178238
• 负责人: KENNETH M PETERS
• 金额: $ 8.85万
• 依托单位: WILLIAM BEAUMONT HOSPITAL RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178238
• 关键词: Bacillus Calmette Guerin vaccine; clinical research; cytokine; enzyme linked immunosorbent assay; human subject; human therapy evaluation; immunomodulators; immunotherapy; interstitial cystitis; longitudinal human study; placebos; prognosis; urinalysis

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.

间质性膀胱炎（IC）是一种严重的膀胱衰弱疾病，病因不明且无法治愈。最近一项使用膀胱内注射卡介苗 (BCG) 治疗 IC 的双盲试验表明，单次 6 周的 BCG 疗程的临床缓解率为 60%。当对 BCG 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，但 89% 的受试者仍保持良好的反应。这种治疗的持久性使人们推测膀胱内注射卡介苗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 2 型辅助 T 细胞 (Th-2) 反应介导的。 IC 受试者尿液中的细胞因子分析显示，IL-6 和 IL-2 抑制剂的水平升高，表明存在 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 病因学中的作用仍存在争议。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化为 Th-1 特征而有效，从而导致修复状况和长期临床反应。具体来说，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) 以盲法确定尿细胞因子在每周六次滴注卡介苗（BCG）或安慰剂期间以及在 6 个月的随访期间定期的变化； 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是否可以预测膀胱内 BCG 治疗的临床反应。这项研究将涉及参加我们目前膀胱内 BCG 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测定一式三份测定，并根据尿肌酸标准化。研究结果将通过非参数方法进行分析。此外，还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。通过关联膀胱内 BCG 治疗之前、期间和之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。