Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky Medical Center, University of Kentucky, Lexington, KY 40536, USA.
J Immunol. 2011 Mar 15;186(6):3726-34. doi: 10.4049/jimmunol.1003343. Epub 2011 Feb 4.
Murine syngeneic graft-versus-host disease (SGVHD) initiates colon and liver inflammation following lethal irradiation, reconstitution with syngeneic bone marrow transplantation, and therapy with the immunosuppressive agent cyclosporine A. Previous studies have demonstrated that the inducible disease is mediated by CD4(+) T cells with increased reactivity of peripheral and liver-associated lymphocytes against intestinal microbial Ags. In the current report, studies were performed to analyze the specificity of the CD4(+) T cell response of T cells isolated from diseased animals and to determine the in vivo role of the microbiota to the development of SGVHD. Increased major histocompatibility Ag (MHC) class II-restricted responsiveness of SGVHD CD4(+) T cells against microbial Ags isolated from the ceca of normal animals was observed. The enhanced proliferative response was observed in the CD62L(-) memory population of CD4(+) T cells. To determine the role of the bacterial microbiota in the development of murine SGVHD, control and CsA-treated bone marrow transplantation animals were treated with broad-spectrum antibiotics (metronidazole, ciprofloxacin) after transplantation. Cyclosporine A-treated animals that were given antibiotic therapy failed to develop clinical symptoms and pathological lesions in the target tissues characteristic of SGVHD. Furthermore, the reduction in intestinal bacteria resulted in the elimination of the enhanced antimicrobial CD4(+) T cell response and significantly reduced levels of the inflammatory cytokines, IFN-γ, IL-17, and TNF-α. The elimination of the disease-associated inflammatory immune responses and pathology by treatment with broad-spectrum antibiotics definitively links the role of the microbiota and microbial-specific immunity to the development of murine SGVHD.
鼠同种异体移植物抗宿主病 (SGVHD) 在致死性照射、同种异体骨髓移植重建和免疫抑制剂环孢素 A 治疗后引发结肠和肝脏炎症。先前的研究表明，这种诱导性疾病是由 CD4(+) T 细胞介导的，外周和肝脏相关淋巴细胞对肠道微生物抗原的反应性增加。在本报告中，进行了研究以分析来自患病动物的 T 细胞的 CD4(+) T 细胞反应的特异性，并确定微生物群在 SGVHD 发展中的体内作用。观察到来自正常动物盲肠的微生物抗原对 SGVHD CD4(+) T 细胞的主要组织相容性 Ag (MHC) Ⅱ类限制反应性增加。在 CD4(+) T 细胞的 CD62L(-) 记忆群体中观察到增强的增殖反应。为了确定细菌微生物群在鼠 SGVHD 发展中的作用，在移植后用广谱抗生素（甲硝唑、环丙沙星）治疗对照和 CsA 处理的骨髓移植动物。接受抗生素治疗的 CsA 处理动物未能发展出具有 SGVHD 特征的靶组织的临床症状和病理损伤。此外，肠道细菌的减少导致增强的抗微生物 CD4(+) T 细胞反应消除，并显著降低炎症细胞因子 IFN-γ、IL-17 和 TNF-α的水平。广谱抗生素治疗消除与疾病相关的炎症免疫反应和病理学，明确将微生物群和微生物特异性免疫的作用与鼠 SGVHD 的发展联系起来。
