Immune Mechanism Underlying CXCR3 and its Ligand Mediated Interstitial Cystitis

描述（由申请人提供）：迫切需要针对间质性膀胱炎（IC）（一种慢性、复发性和严重衰弱性膀胱疾病）的新干预和预防策略。据估计，美国每年报告约100万例IC病例，其中90%发生在女性中。在初步研究中，我们发现，与正常健康供体相比，IC患者血清CXCR 3配体水平与急性期和炎性细胞因子一起沿着上调。相应地，我们发现CXCR3及其配体在实验性自身免疫性膀胱炎（EAC）诱导小鼠慢性IC后，在髂淋巴结和膀胱的炎症部位上调。我们还发现，在慢性IC小鼠的全身和粘膜部位的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，抗CXCL10抗体治疗阻碍了慢性IC的发展。在慢性IC后的小鼠中，抗CXCL10 Abs治疗后，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性Th1细胞因子也减少。这些结果为我们的中心假设提供了强有力的理论基础，即确定造血细胞、骨髓细胞和非造血细胞的CXCR3和CXCR3配体的差异表达是否介导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。三个具体目标将用于阐明CXCR3和CXCR3配体在IC进展过程中的确切作用。

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.