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.

在患有CD的患者中，对微生物抗原的免疫反应可能与不同 病理生理机制以及独特的临床表型。我们已经表明，CD患者可能会失去对特定细菌抗原的耐受性，并且可以根据对某些抗原的响应血清抗体表达的模式聚集成组。但是，基因型与侵袭性临床表型有关，但是，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紧密相关。对更多的微生物抗原（CD HighR）反应最多的患者患有一种疾病病程，该病程从轻度到重度发展，可能需要手术，而对相反的患者（CDLOWR）对这些抗原的患者（CDLOWR）对患有轻度，非疾病病程的这些抗原。我们进一步表明，血清对这些微生物抗原的反应可用于选择通过细菌菌群的治疗操纵来改善临床症状的患者，无论是通过促或抗生素治疗和/或粪便流的手术旁路。最近，我们合作研究了导致对独特鞭毛蛋白CBIRL的血清抗体反应的研究。我们表明患有 对特定微生物抗原的最高反应对这种新型细菌抗原的振幅反应最高。因此，这些研究现已证明，通过血清抗体表达测量的自适应免疫反应对微生物抗原的数量和幅度可用于将CD群体化为具有侵袭性疾病和良性疾病患者的组。在小鼠模型中平行研究的结果表明，在设计的小鼠中引起了最严重和最严重的疾病，其TH1反应和缺乏调节功能。在下一个拨款周期中要检验的假设是，对最大数量的微生物抗原的最高振幅反应将反映出病理生理机制，导致CD的侵略性形式，其特征是Th 1的反应至少是由于先天性免疫功能或缺陷而在产生和/或功能中产生的，并且由免疫细胞群的产生和/或功能变化而改变。我们将：1）确定从头开始和/或体外产生的Th1功能和/或相关因素是否最高。 2）确定是否 随着共生相关的分子模式（CAMP）激活，专门针对CD-HIGHR患者，单核细胞/单核细胞衍生的树突状细胞（MDDC）相关的TH1产生的细胞因子的产生和/或炎性细胞因子减少了。 3）确定在CDHIGHR患者中特别降低了CD4+ CD25+或TR1调节细胞的频率和/或功能。 4）确定用抗生素改变共生细菌的水平/组成是否会为CD-highR患者提供最大的临床益处。