IMMUNOPATHOLOGY & AGGRESSIVE CROHN'S DISEASE IMMUNOPHENOTYPE

免疫病理学

• 批准号: 7487326
• 负责人: Stephan R. Targan
• 金额: $ 22.16万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487326
• 关键词: Animal Model; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Formation; Antigens; Bacterial Antigens; Benign; Bypass; Cells; Clinical; Crohn' s disease; Defect; Dendritic Cells; Disease; Engineering; Flagellin; Frequencies; Generations; Genes; Genetic; Genotype; Grant; Human; Immune response; Immunologics; Immunophenotyping; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Measures; Molecular; Mus; Nature; Numbers; Operative Surgical Procedures; Patients; Pattern; Play; Population; Progressive Disease; Role; Series; Serological; Serum; Stream; Symptoms; Testing; Therapeutic; To specify; Variant; clinical phenotype; commensal microbes; cytokine; immune function; immunopathology; microorganism antigen; monocyte; mouse model; novel; response

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应答可能与不同的 病理生理机制以及独特的临床表型。我们已经证明，CD患者可能会失去对特定细菌抗原的耐受性，并且可以根据响应某些抗原的血清抗体表达模式聚集成组。基因型与侵袭性临床表型相关，然而，我们最近发现对微生物抗原的血清学应答与病理生理机制更密切相关。对更多数量的微生物抗原应答最多的患者（CD highR）的病程从轻度进展到重度，可能需要手术，而对这些抗原无应答的患者（CD lowR）的病程为轻度、非进展性。我们进一步表明，对这些微生物抗原的血清应答可用于选择通过细菌植物群的治疗性操作（通过亲或抗生素治疗和/或粪便流的手术旁路）而改善临床症状的患者。最近，我们合作的研究导致了对独特鞭毛蛋白CBirl的血清抗体反应的发现。我们发现， 对特定微生物抗原的最高应答也具有对这种新细菌抗原的最高幅度应答。因此，这些研究现在已经证明，通过血清抗体表达测量的对微生物抗原的适应性免疫应答的数量和幅度，可以用于将CD人群分为侵袭性疾病患者和良性疾病患者。在小鼠模型中进行的平行研究的结果表明，最严重和进行性疾病是在被改造为具有最高Th 1应答和缺乏调节功能的小鼠中引起的。在该下一个资助周期中要测试的假设是，对最大数量的微生物抗原的最高幅度应答将反映导致CD的侵袭性形式的病理生理机制，其特征在于至少部分由先天免疫功能改变或免疫调节细胞群的生成和/或功能缺陷引起的增强的Th 1应答。我们将：1）确定从头和/或体外产生的Th 1功能和/或相关因子是否在CD-highR患者中最高。2)确定是否 单核细胞/单核细胞衍生的树突状细胞（MDDC）相关的Th 1产生细胞因子增强，和/或炎性细胞因子减少，特别是在CD-高R患者中。3)确定CD 4 + CD 25+或Tr 1调节细胞的频率和/或功能是否在CDhighR患者中特异性降低。4)确定用抗生素改变肠道细菌的水平/组成是否会为CD-highR患者提供最大的临床获益。