B CELL IMMUNOREGULATION IN CROHN 'S DISEASE

克罗恩病中的 B 细胞免疫调节

• 批准号: 7024926
• 负责人: JONATHAN BRAUN
• 金额: $ 23.16万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024926
• 关键词: B lymphocyte; Crohn' s disease; bactericidal immunity; cellular immunity; colitis; cytogenetics; cytoprotection; flow cytometry; gastric mucosa; helper T lymphocyte; immune response; immunoregulation; laboratory mouse; leukocyte activation /transformation; mixed tissue /cell culture; mucosal immunity; natural killer cells; suppressor T lymphocyte

Enteric commensal bacterial products elicit immune responses that are key to the tissue-damaging inflammation in humans and animal models with IBD. In the last grant cycle, we collaborated with Project 2 to identify microbial products that reveal a loss of tolerance in CD patients to specific bacterial antigens, and that such patients cluster into groups defined by patterns of serum antibody expression. In particular, patient groups expressing an antibody pattern of the highest amplitude and antigenic diversity (CD-highR) defined a patient subset with uniquely aggressive disease. In mouse models of colitis, the most severe and progressive disease occurs in mice engineered for both high Th1 responses and a lack of regulatory function. Our mouse studies have contributed to the recognition of a "surveillance" subset of B cells that particpate in mucosal immunoregulation and colitis protection through interaction with NKT cells, and CD4+CD8+double-positive (DP) T cells with suppression of Th1 colitis. The hypothesis tested in this next grant cycle is that mucosal surveillance B cells, by their efficient activation of regulatory NKT and DP T cells, promote protection against inflammation and mucosal tissue damage. Accordingly, we predict that impaired formation/function of this B cell subset represents a mode of immunoregulatory failure leading to the aggressive form of human CD observed in the CDhighR patient population. In Aims 1-3, we collaborate with Project 4 in the mouse to develop analytic tools and experimental approaches that model this hypothesis: (1) To define pharmacologic factors that regulate formation of surveillance B cells; (2) To identify the subset of B cells and their mode of interaction with NKT and DP T cells; (3) To test whether attenuated B cell immunoregulation is a susceptibility trait for aggressive colitis. In Aim 4, we collaborate with Projects 1, 2, and Core B to translate our analytic tools to the human, and directly test the hypothesis that the CD-highR subset of human CD patient patients is distinguished by impaired B-cell interaction with immunoregulatory T cell subsets.

肠道细菌产物引起免疫应答，这是IBD人类和动物模型中组织损伤性炎症的关键。在上一个资助周期中，我们与项目2合作，鉴定了微生物产物，这些微生物产物揭示了CD患者对特定细菌抗原的耐受性丧失，并且这些患者聚集成由血清抗体表达模式定义的组。特别是，表达最高幅度和抗原多样性（CD-highR）抗体模式的患者群体定义了具有独特侵袭性疾病的患者亚群。在结肠炎小鼠模型中，最严重和进行性疾病发生在设计为高Th 1应答和缺乏调节功能的小鼠中。我们的小鼠研究有助于认识到一个“监视”子集， 通过与NKT细胞相互作用参与粘膜免疫调节和结肠炎保护的B细胞，以及抑制Th 1结肠炎的CD 4 + CD 8+双阳性（DP）T细胞。 在下一个资助周期中测试的假设是粘膜监视B细胞通过其有效激活调节性NKT和DP T细胞，促进对炎症和粘膜组织损伤的保护。因此，我们预测该B细胞亚群的形成/功能受损代表免疫调节失败的模式，导致在CD highR患者群体中观察到的人CD的侵袭性形式。在目标1-3中，我们与项目4合作，在小鼠中开发模拟该假设的分析工具和实验方法：（1）确定调节监视B细胞形成的药理学因素;（2）鉴定B细胞亚群及其与NKT和DP T细胞的相互作用模式;（3）检测B细胞免疫调节减弱是否为侵袭性结肠炎的易感特征。在目标4中，我们与项目1、2和核心B合作，将我们的分析工具转化为人类，并直接检验人类CD患者的CD-highR亚群通过受损的B细胞与免疫调节T细胞亚群的相互作用来区分的假设。