Initiation and Regulation of Chronic Autoimmune Prostate Inflammation

描述（由申请人提供）：前列腺慢性非细菌性炎症与多种前列腺疾病相关，包括慢性前列腺炎-慢性盆腔疼痛综合征（CP-CPPS）、良性前列腺增生（BPH）和前列腺癌。前列腺疾病和炎症之间的关联的多样性为更好地理解前列腺炎症的起源和调节提供了强有力的理论基础。虽然前列腺炎症的原因尚未最终确定，但T细胞特异性自身免疫性已在临床和动物模型中与前列腺炎症过程相关。因此，需要研究定义自身免疫性前列腺炎症及其调节，以更好地了解炎症过程，并确定潜在的干预点，以减少或消除炎症。我们开发了一种新的转基因小鼠模型，专门表达膜结合卵清蛋白的前列腺上皮细胞研究前列腺炎症过程及其调控。在过去的资助期间的研究表明，髓源性抑制细胞（MDSC）在前列腺炎症的调节中发挥重要作用。在反应的前10- 14天期间，观察到MDSC作为炎性浸润中的主要细胞类型。抑制MDSC对T细胞的调节增强炎症。值得注意的是，观察到功能性MDSC定位于发炎的前列腺，而脾和肝中表型相同的细胞被分类为前体细胞，为鉴别与MDSC功能相关的途径奠定了基础。本文所示的初步数据显示，鉴定了一种新的炎症和MDSC功能的肽抑制剂，其将前列腺炎症中的MDSC功能和炎性细胞因子水平与p38信号传导途径联系起来。此外，阳离子氨基酸转运蛋白的功能，提供L-Arg MDSC进行了鉴定。最后，生成的数据表明，与对照组相比，CP-CPPS患者外周血中MDSC升高，表明在人类疾病中的作用。这些数据为MDSC的细胞因子产生和T细胞调节对前列腺炎症及其调节至关重要的假设提供了基础。此外，MDSC功能在炎症部位的定位提供了一个基础， 差异鉴定与MDSC功能相关的其他途径。本申请中概述的研究提出进一步定义MDSC的调节途径，目的是开发新的方法来控制POET-3模型和CP-CPPS患者的临床标本中的前列腺炎症。为此，提出了以下具体目标。具体目标1。在POET-3模型和CP-CPPS临床环境中定义骨髓源性抑制细胞通路/分子，以控制前列腺炎症。假设：了解控制MDSC调节T细胞应答和细胞因子产生的细胞分子/途径将为剖析MDSC在调节前列腺炎症中的功能意义提供途径。具体目标2。明确髓源性抑制细胞调节对前列腺炎症和前列腺组织病理学的影响。假设：骨髓来源的抑制细胞，虽然存在早期和短暂的，是通过抑制T细胞反应和控制炎症部位的细胞因子的产生来调节前列腺炎症的核心。

DESCRIPTION (provided by applicant): Chronic non-bacterial inflammation of the prostate is associated with multiple prostate diseases including chronic prostatitis-chronic pelvic pain syndrome (CP-CPPS), benign prostatic hyperplasia (BPH), and prostate cancer. The multiplicity of associations between prostate diseases and inflammation provide a strong rationale for better understanding the origin and regulation of prostate inflammation. While the cause of prostate inflammation has not been conclusively determined, T cell specific autoimmunity has been linked to prostate inflammatory processes both clinically and in animal models. Thus, studies to define autoimmune prostate inflammation and its regulation are needed to provide a better understanding of the inflammatory process and to identify potential points of intervention to reduce or eliminate inflammation. We developed a novel transgenic mouse model expressing membrane bound ovalbumin exclusively on prostate epithelial cells to investigate prostate inflammatory processes and its regulation. Studies during the past funding period showed an important role for myeloid-derived suppressor cells (MDSC) in the regulation of prostate inflammation. MDSC were observed as the dominant cell type in the inflammatory infiltrate during the first 10- 14 days of the response. Inhibition of MDSC regulation of T cells enhanced inflammation. Notably, functional MDSC were observed to be localized to the inflamed prostate, whereas phenotypically identical cells in the spleen and liver were classified as precursor cells, setting the stage for differential identification of pathways linked to MDSC function. Preliminary data shown herein show that a novel peptide inhibitor of inflammation and MDSC function was identified that links MDSC function and inflammatory cytokine levels in prostate inflammation to the p38 signaling pathway. Moreover, the cationic amino acid transporter that functions to deliver L-Arg to MDSC was identified. Finally, data were generated demonstrating an elevation of MDSC in the peripheral blood of patients with CP-CPPS compared to controls, suggesting a role in human disease. These data provide a foundation for the hypothesis that cytokine production and T cell regulation by MDSC are central to prostate inflammation and its regulation. Further, localization of MDSC function to the site of inflammation provides a basis for differentially identifying additional pathways linked to MDSC function. Studies outlined in this application propose to further define the regulatory pathways of MDSC with the intent of developing novel approaches to controlling prostate inflammation both in the POET-3 model and clinical specimens from CP-CPPS patients. To this end the following specific aims are proposed. Specific Aim 1. Define myeloid-derived suppressor cell pathways/molecules in the POET-3 model and clinical setting of CP-CPPS central to controlling prostate inflammation. Hypothesis: Understanding the cellular molecules/pathways controlling MDSC regulation of T cell responses and cytokine production will provide avenues for dissecting functional implications of MDSC in modulating prostate inflammation. Specific Aim 2. Define the impact of myeloid-derived suppressor cell regulation on prostate inflammation and prostate histopathology. Hypothesis: Myeloid-derived suppressor cells, although present early and transiently, are central to the regulation of prostate inflammation through inhibition of T cell responses and control of cytokine production at the inflammatory site.