T cells in Chronic Pelvic Pain

T 细胞在慢性盆腔疼痛中的作用

• 批准号: 8789163
• 负责人: PRAVEEN THUMBIKAT
• 金额: $ 33.6万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789163
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Affect; American; Animals; Anogenital region; Antigen Targeting; Antigens; Autoimmune Process; Bacteria; Bacterial Infections; Bacterial Prostatitis; Biological Assay; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Chronic; Chronic Prostatitis; Clinic; Clinical; Coculture Techniques; Diagnosis; Disease; Dysuria; Escherichia coli; Etiology; Exhibits; Future; Health; Human; IL2RA gene; Immune Sera; Immune response; Immunotherapy; In Vitro; Inbred NOD Mice; Infection; Inflammatory Response; Interferons; Interleukin-17; Interleukin-4; Lead; Massage; Mediating; Medical; Methodology; Methods; Modeling; Morbidity - disease rate; Mus; Names; Nature; Pain; Patients; Pelvic Pain; Peripheral Blood Mononuclear Cell; Phenotype; Prostate; Prostatic; Recruitment Activity; Regulatory T-Lymphocyte; Resolution; Role; Self Tolerance; Self-Injurious Behavior; Serum; Source; Symptoms; Syndrome; T cell response; T-Lymphocyte; Testing; Testis; United States; United States National Institutes of Health; Urine; chemokine; chronic pain; chronic pelvic pain; injured; macrophage; mast cell; men; microbial; mouse model; neutrophil; novel; penis; peripheral blood; prostatitis; receptor; response; secondary infection; targeted treatment; trafficking

DESCRIPTION (provided by applicant): Chronic pelvic pain is the hallmark of patients with Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), a category of prostatitis that is a significant source of morbidity in American men. A microbial etiology for CP/CPPS has long been postulated but a cause and effect relationship has been difficult to demonstrate due to the chronic nature of the syndrome, the often-delayed diagnosis, and the confounding presence of bacteria in prostates of healthy men. We recently identified a clinical E. coli strain named CP1 from a patient with chronic pelvic pain that was capable of faithfully replicating the chronic pain state in a mouse model of bacterial prostatitis. The CP1 strain infected the prostate of NOD and B6 mice, resulting in an inflammatory response in both strains but inducing the chronic pain state only in NOD mice. Chronic pain persisted even in the absence of detectable bacterial colonization. Our preliminary studies show that the pain is transferable using CD4+ T cells and is associated with a predominant Th1/Th17 immune response. In contrast, CP1 infection in the non-pain permissible B6 mice induced CD4 T cells with an IL-4 response and elevated levels of FoxP3+ CD25+ regulatory T cells. Infection with NU14, a non-pain inducing E. coli strain also resulted in elevated levels of FoxP3+ CD25+ regulatory T cells in both the NOD and B6 mice, suggesting an association between the presence of regulatory T cells and absence of pelvic pain. These studies lead us to hypothesize that bacterial-induced chronic pelvic pain is mediated by IFN-¿ and IL-17 secreting CD4+ T cells and suppressed by regulatory T cells in the prostate. We will address our hypothesis using the following specific aims: 1. identifying the functional role of Th1/Th17 T cells in chronic pelvic pain. 2. Defining the mechanism of T cell trafficking to the injured prostate. 3. Identifying strategies to promote self-tolerance in the prostate. These studies are expected to result in an understanding of specific mechanisms of chronic pelvic pain in CPPS as well as identification of novel methodologies to effect pain reduction and disease resolution in CPPS patients.

描述(申请人提供)：慢性盆腔疼痛是慢性前列腺炎/慢性盆腔疼痛综合征(CP/CPPS)患者的特征，这是一种前列腺炎，是美国男性发病率的重要来源。长期以来，CP/CPPS的微生物病因学一直被假设，但由于该综合征的慢性性质，诊断经常延误，以及健康男性前列腺中细菌的混杂存在，因果关系很难证明。我们最近从一名慢性盆腔疼痛患者中鉴定出一种名为cp1的临床大肠杆菌菌株，它能够忠实地复制慢性疼痛。 在细菌性前列腺炎小鼠模型中的状态。CP1菌株感染NOD和B6小鼠的前列腺，导致两种菌株的炎症反应，但只在NOD小鼠引起慢性疼痛状态。即使在没有可检测到的细菌定植的情况下，慢性疼痛仍然存在。我们的初步研究表明，疼痛可以通过CD4+T细胞转移，并与主要的Th1/Th17免疫反应有关。相反，在不允许疼痛的B6小鼠中，CP1感染诱导了具有IL-4反应的CD4T细胞和高水平的FoxP3+CD25+调节性T细胞。感染不会引起疼痛的大肠杆菌NU14也导致NOD和B6小鼠体内FoxP3+CD25+调节性T细胞水平升高，这表明调节性T细胞的存在与盆腔疼痛的消失之间存在关联。这些研究使我们假设，细菌引起的慢性盆腔疼痛是由分泌CD4+T细胞的干扰素和IL-17介导的，并受到前列腺中调节性T细胞的抑制。我们将通过以下具体目标来解释我们的假说：1.确定Th1/Th17 T细胞在慢性盆腔疼痛中的功能作用。2.明确T细胞向受损前列腺的转运机制。3.确定促进前列腺自我耐受的策略。这些研究预计将有助于了解慢性盆腔疼痛在CPPS中的具体机制，并确定新的方法来减轻CPPS患者的疼痛和缓解疾病。