IMMUNOPATHOLOGY--CROHN'S DISEASE IMMUNOPHENOTYPE

免疫病理学--克罗恩病免疫表型

• 批准号: 7024925
• 负责人: Stephan R. Targan
• 金额: $ 22.41万
• 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/7024925
• 关键词: Crohn' s disease; T lymphocyte; antibacterial antibody; antigen antibody reaction; antigen presentation; bacteria infection mechanism; bacterial antigens; biopsy; cellular immunity; helper T lymphocyte; human subject; immune response; immunogenetics; immunopathology; immunoregulation; phenotype; regulatory gene; serology /serodiagnosis; virulence

Among patients with CD, immune responses to microbial antigens may be related to different pathophysiologic mechanisms as well as unique clinical phenotypes. We have shown that CD patients can lose tolerance to specific bacterial antigens and can be clustered into groups depending on patterns of serum antibody expression in response to certain antigens. Genotypes have been associated with aggressive clinical phenotypes, however, we have recently shown that serologic responses to microbial antigens are more closely related to the pathophysiologic mechanisms. Patients who respond the most, to a greater number of microbial antigens (CD highR), have a disease course that progresses from mild to severe and is likely to require surgery, as opposed patients who are non-responsive (CDlowR) to these antigens, who have a mild, non-progressive, disease course. We further showed that serum responses to these microbial antigens can be used to select patients whose clinical symptoms ameliorate with therapeutic manipulation of the bacterial flora, either by pro- or antibiotic therapy and/or surgical bypass of the fecal stream. Recently, we collaborated in studies that led to the discovery of serum antibody responses to a unique flagellin, CBirl. We showed that patients with the highest responses to specified microbial antigens have the highest amplitude responses to this novel bacterial antigen, as well. Thus, these studies have now demonstrated that the number and magnitude of adaptive immune responses to microbial antigens, as measured by serum antibody expression, can be used to substratify the CD population into groups of patients with aggressive disease and those with benign disease. Results from parallel studies in mouse models demonstrated that the most severe and progressive disease was elicited in the mice engineered to have the highest Th1 responses and a lack of regulatory function. The hypothesis to be tested in this next grant cycle is that the highest amplitude responses to the greatest number of microbial antigens will reflect pathophysiologic mechanisms leading to an aggressive form of CD characterized by enhanced Th 1 responses at least partially resulting from altered innate immune function or defect(s) in generation and/or function of immunoregulatory cell populations. We will: 1) Determine whether de novo and/or in vitro generated Th1 function and/or associated factors are the highest in CD-highR patients. 2) Determine whether monocyte/monocyte-derived dendritic cell (MDDC)-associated Th1 generating cytokines are enhanced, and/or inflammatory cytokines reduced, following commensal associated molecular pattern (CAMP) activation, specifically in CD-highR patients. 3) Determine whether the frequency and/or the function of CD4+CD25+ or Tr1 regulatory cells are diminished specifically in CDhighR patients. 4) Determine whether altering the level/composition of commensal bacteria with antibiotics will provide the greatest clinical benefit in CD-highR patients.

在 CD 患者中，对微生物抗原的免疫反应可能与不同的 病理生理机制以及独特的临床表型。我们已经证明，克罗恩病患者可能会失去对特定细菌抗原的耐受性，并且可以根据响应某些抗原的血清抗体表达模式进行分组。基因型与侵袭性临床表型相关，然而，我们最近表明，对微生物抗原的血清学反应与病理生理机制更密切相关。对大量微生物抗原 (CD highR) 反应最多的患者，其病程从轻度到重度进展，可能需要手术，而对这些抗原无反应 (CDlowR) 的患者则相反，病程轻微、非进行性的患者。我们进一步表明，对这些微生物抗原的血清反应可用于选择通过对细菌菌群进行治疗操作（通过前体或抗生素治疗和/或粪便流手术旁路）来改善临床症状的患者。最近，我们合作进行的研究发现了血清抗体对一种独特的鞭毛蛋白 CBirl 的反应。我们表明患者 对特定微生物抗原的最高反应也对这种新型细菌抗原具有最高幅度的反应。因此，这些研究现已证明，通过血清抗体表达测量的对微生物抗原的适应性免疫反应的数量和程度，可用于将 CD 人群细分为侵袭性疾病患者和良性疾病患者。小鼠模型的平行研究结果表明，经过改造而具有最高 Th1 反应且缺乏调节功能的小鼠引发了最严重和进展性疾病。在下一个资助周期中要测试的假设是，对最大数量微生物抗原的最大幅度反应将反映导致 CD 侵袭性形式的病理生理机制，其特征是 Th 1 反应增强，至少部分是由于先天免疫功能改变或免疫调节细胞群的生成和/或功能缺陷。我们将： 1) 确定 CD-highR 患者中从头和/或体外产生的 Th1 功能和/或相关因子是否最高。 2）判断是否 共生相关分子模式 (CAMP) 激活后，单核细胞/单核细胞衍生树突细胞 (MDDC) 相关 Th1 生成细胞因子增强，和/或炎性细胞因子减少，特别是在 CD-highR 患者中。 3) 确定 CD4+CD25+ 或 Tr1 调节细胞的频率和/或功能是否在 CDhighR 患者中特异性减少。 4) 确定用抗生素改变共生细菌的水平/组成是否会给 CD-highR 患者带来最大的临床益处。