Immune Mechanism Underlying CXCR3 and its Ligand Mediated Interstitial Cystitis

CXCR3及其配体介导间质性膀胱炎的免疫机制

• 批准号: 8537713
• 负责人: Udai P. Singh
• 金额: $ 12.33万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537713
• 关键词: Abdomen; Acute; Affect; Animal Model; Antibodies; Autoimmune Process; Autoimmunity; Biological; Bladder; CD4 Positive T Lymphocytes; CXCL10 gene; CXCL11 gene; CXCR3 gene; Cells; Characteristics; Chronic; Chronic interstitial cystitis; Clinical; Common iliac lymph node; Complex; Cyclophosphamide; Cystitis; Dendritic Cells; Development; Disease; Epithelial Cells; Etiology; Functional disorder; Hematopoietic; Human; Immune; Increased frequency of micturition; Inflammation; Inflammatory; Interstitial Cystitis; Intervention; Knockout Mice; Leukocytes; Ligands; Lymphocyte; Mediating; Messenger RNA; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Output; Pain; Pathogenesis; Pathology; Patients; Phase; Phenotype; Prevention strategy; Production; Reflex action; Relapse; Reporting; Role; Serum; Site; Smooth Muscle; Spleen; Stress; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Treatment Protocols; United States; Urine; Visit; Woman; burden of illness; cost; cytokine; granulocyte; improved; innovation; interest; mast cell; micturition urgency; mucosal site; neutrophil; novel; response; theories

DESCRIPTION (provided by applicant): There is immense need for new intervention and prevention strategies against interstitial cystitis (IC), a chronic, relapsing, and severely debilitating disease of the urinary bladder. Estimates indicate that ~1 million cases of IC are reported annually in the United States, with 90% of these occurring in women. In a preliminary study, we showed that, along with acute phase and inflammatory cytokines, serum CXCR3 ligand levels are up-regulated in IC patients as compared with normal healthy donors. Correspondingly, we showed that CXCR3 and its ligands are up-regulated at sites of inflammation in the iliac lymph nodes and urinary bladder following experimental autoimmune cystitis (EAC) induction of chronic IC in mice. We also show that the number of CD4+ T cells, mast cells, and neutrophils is increased at systemic and mucosal sites during chronic IC in mice. Most importantly, we have demonstrated that anti-CXCL10 Abs treatment hinders the development of chronic IC. Urinary bladder CD4+ T cells, mast cells, neutrophil infiltrates, local production of CXCR3 ligand, and systemic Th1 cytokines were also reduced following anti-CXCL10 Abs treatment in mice after chronic IC. These results provide a strong rationale for our central hypothesis, which is to determine whether differential expression of CXCR3 and CXCR3 ligands by hematopoietic, myeloid, and non-hematopoietic cells mediates the induction and progression of IC. Targeting CXCR3 and its ligands may serve as a potential therapeutic option for IC. Three specific aims will be used to elucidate the precise role of CXCR3 and CXCR3 ligand during IC progression.

描述（由申请人提供）：间质性膀胱炎（IC）是一种慢性、复发性和严重的膀胱衰弱性疾病，目前迫切需要新的干预和预防策略。据估计，美国每年报告的IC病例约为100万例，其中90%为女性。在一项初步研究中，我们发现，与正常健康供体相比，IC患者的血清CXCR3配体水平与急性期和炎症细胞因子一起上调。相应地，我们发现在实验性自身免疫性膀胱炎（EAC）诱导小鼠慢性IC后，CXCR3及其配体在髂淋巴结和膀胱炎症部位上调。我们还发现，小鼠慢性IC期间，全身和粘膜部位的CD4+ T细胞、肥大细胞和中性粒细胞的数量增加。最重要的是，我们已经证明了抗cxcl10抗体治疗阻碍慢性IC的发展。慢性IC后小鼠膀胱CD4+ T细胞、肥大细胞、中性粒细胞浸润、CXCR3配体的局部产生和全身Th1细胞因子也在抗cxcl10抗体治疗后减少。这些结果为我们的中心假设提供了强有力的理论基础，该假设是确定CXCR3和CXCR3配体在造血、骨髓、和非造血细胞介导IC的诱导和进展。靶向CXCR3及其配体可能是IC的潜在治疗选择。三个特定目的将用于阐明CXCR3和CXCR3配体在IC进展中的确切作用。