MUCOSAL T-CELLS IN EARLY&LATE PEDIATRIC CROHN'S DISEASE

提案（改编自申请人的摘要）：本项目的总体目标 项目是功能和表型特征肠粘膜T细胞 新发和长期克罗恩病（CD）儿童，以及 利用这些信息指导制定新的裁军战略 诊断、患者分层和早期医疗干预。 CD是一个 胃肠道的毁灭性终身慢性炎症性破坏 最常在青少年和年轻人中诊断的道。 由于CD的病因尚不明确，诊断依赖于 X线、内窥镜检查发现的破坏性粘膜变化的识别 和/或组织组织学。 最近的临床试验表明， 免疫调节剂治疗可改善CD患者的临床结局 儿童，但早期医疗干预可能会受到诊断滞后的阻碍 长达18个月。 基本调查也表明， 存在于“早期”和“晚期”阶段之间的细胞和分子机制中 肠道慢性炎症，进一步强调需要 在诊断时以及在长期CD中进行调查。 在过去的四年里，调查人员进行了系统的 儿童内镜活检组织中T淋巴细胞的研究 CD以及非炎性肠病（IBD）炎症， 正常对照者 他们定义了体外T细胞生长的独特模式 以及对白细胞介素-2（IL-2）应答的增殖，其中CD、粘膜T- 细胞显示出显著增强的体外生长（J.Peds.，133：675- 81，1998）。 最近的流式细胞术分析粘膜T细胞表型， 显示免疫记忆标志物（CD 45 RA，CD 45 RO）和归巢标志物（L- 选择素）区分慢性炎症的“早期”和“晚期”阶段， CD儿童 因此，该提案的中心假设是： 粘膜T细胞功能和表型的表征将允许 及时诊断，并分为“早期”和“晚期”阶段 儿童CD的慢性炎症。 这一假设将得到检验， 以下三个具体目标。 目的1是粘膜的表征 CD早期诊断中T细胞体外生长的横断面研究 验证、纵向跟踪和风险儿童评估。 目的2 是粘膜T细胞表型和功能的表征， 和晚期CD，分析粘膜T细胞亚群和细胞因子产生。 目的3是评估早期免疫调节治疗对临床的影响， 结果以及与粘膜T细胞表型和功能的相关性 在24个月的纵向随访中，诊断为CD的患者。 K23 指导以患者为导向的临床研究职业发展奖将不会 仅定义了研究不足的免疫发病机制的基本领域 在儿科CD领域，它还将允许申请人获得关键的 进行高质量翻译所需的培训和专业知识 research.

PROPOSAL (Adapted from the applicant's abstract): The overall goal of this project is to functionally and phenotypically characterize gut mucosal T-cells in children with new onset as well as longstanding Crohn's disease (CD), and use this information in guiding the development of new strategies for CD diagnosis, patient substratification and early medical intervention. CD is a devastating lifelong chronic inflammatory destruction of the gastrointestional tract that is most frequently diagnosed in adolescents and young adults. Because the cause of CD remains undefined, diagnosis relies on the identification of destructive mucosal changes identified on x-ray, endoscopy and/or tissue histology. Recent clinical trials suggest that early immunomodulator therapy results in an improved clinical outcome in CD children, but early medical intervention may be hindered by a lag in diagnosis of up to 18 months. Basic investigation also suggests significant differences exist in cellular and molecular mechanisms between "early" and "late" phases of chronic inflammation in the intestine, further emphasizing the need for investigation both at the time of diagnosis as well as in longstanding CD. Over the past four years, the investigators have conducted a systematic investigation of mucosal T-cells isolated from endoscopic biopsies in children with CD as well as non-inflammatory bowel disease (IBD) inflammation and normal controls. They have defined unique patterns of in vitro T-cell growth and proliferation in response to interleukin-2 (IL-2), where CD, mucosal T- cells demonstrate significantly enhanced in vitro growth (J. Peds., 133: 675- 81, 1998). Recent flow cytometric analysis of mucosal T-cell phenotype has shown that markers of immunologic memory (CD45RA, CD45RO) and homing (L- selectin) differentiate "early" and "late" phases of chronic inflammation in CD children. Thus, the central hypothesis of this proposal is: Characterization of mucosal T-cell function and phenotype will allow for prompt diagnosis as well as substratification into "early" and "late" phases of chronic inflammation in pediatric CD. This hypothesis will be tested with the following three specific aims. Aim 1 is the characterization of mucosal T-cell in vitro growth in the early diagnosis of CD, with cross-sectional validation, longitudinal follow-up, and evaluation of children at risk. Aim 2 is the characterization of mucosal T-cell phenotype and function during early and late CD with analysis of mucosal T-cell subsets and cytokine production. Aim 3 is to assess the impact of early immunomodulatory therapy on clinical outcome and correlate with mucosal T-cell phenotype and function in newly diagnosed CD patients over a 24-month longitudinal follow-up. Thus, the K23 Mentored Patient-Oriented Clinical Research Career Development Award will not only define fundamental areas of immunopathogenesis in the under-researched area of pediatric CD, it will also allow the applicant to obtain critical training and expertise required to perform high caliber translational research.