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）是一种严重的衰弱的膀胱疾病，是未知的病因，无法治愈。最近使用静脉内芽孢杆菌瓜素（BCG）治疗IC的一项双盲试验表明，BCG的六周课程的临床反应率为60％。当对BCG做出反应的受试者至少持续了两年，尽管没有对IC进行额外的治疗，但仍有89％的受试者仍然有很好的反应。这种治疗的耐用性导致人们推测静脉内BCG可以治疗间质膀胱炎的机制。有证据表明，间质性膀胱炎可能是由膀胱内的T碳细胞类型2（TH-2）反应介导的。来自IC受试者尿液的细胞因子分析显示，白介素-6和白介素-2抑制剂水平升高，表明TH-2反应。此外，在特应性皮炎，TH-2介导的疾病和间质膀胱炎中都发现了类似的自身抗体。但是，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，并且插后BCG通过将细胞因子环境转化为TH-1特征，从而有效，从而导致修复性疾病和长期临床反应。具体而言，这项研究将：1）确定符合NIDDK膀胱炎和卫生控制受试者标准的受试者中的尿液细胞因子谱； 2）以盲目的方式确定六个月的随访期间六个每周滴注杆菌Calmette-guerin（BCG）或安慰剂的尿中细胞因子的变化； 3）将细胞因子的变化与临床反应相关； 4）确定某种细胞因子特征的细胞因子谱是否可以预测对内部BCG治疗的临床反应。这项研究将涉及参加我们目前对IC经误BCG治疗的临床试验的受试者。细胞因子水平将通过酶联免疫吸收测定法确定一式三份，并针对尿肌酸进行标准化。研究结果将通过非参数方法进行分析。此外，将完成接收操作特征分析，以确定预测治疗临床反应的关键细胞因子水平。总而言之，这项研究将确定IC受试者和健康受试者中的细胞因子谱。通过在内部BCG治疗之前，之中和之后，通过将细胞因子水平的变化相关联，我们将确定这些细胞因子在IC中的作用，并利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，具有特定的长期潜力，以开发出更有效的，毒性更少的IC。