Brown G R, Thiele D L
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 75390-9151, USA.
J Clin Immunol. 2000 Sep;20(5):379-88. doi: 10.1023/a:1006676315093.
Administration of a tumor necrosis factor (TNF) inhibitor-encoding adenoviral vector decreases the severity of colonic inflammation in a DBA/2-->B6D2F1 murine model of colonic graft-versus-host disease (GVHD). The present studies evaluated the effect of TNF blockade on the splenic and colonic T-cell responses. cDNA encoding an artificial fusion protein consisting of the extracellular domain of the human 55-kDa receptor for TNF fused to a mouse IgG heavy chain was subcloned into an E1a-deficient adenoviral vector. Following transfer of DBA/2 T cells and bone marrow cells into irradiated B6D2F1 mice, the mice then received either the control adenovirus or the TNF inhibitor-encoding adenovirus. Splenic and colonic lymphocytes were isolated, stained with anti-H-2b, anti-H-2d, anti-CD3, anti-CD4, anti-CD8, and anti-CD45RB antibodies, and analyzed by flow cytometry. Splenic and colonic lymphocyte cytokine profiles also were assessed. More colonic T cells of donor origin were isolated from the control adenovirus recipients than from recipients of the TNF inhibitor encoding adenovirus (P = .027). Fewer CD4+ and CD8+ T cells were observed in colon but not in the spleen in the TNF inhibitor recipients. Fewer CD45RBlow (memory) T cells were observed in the CD4+ colonic lymphocytes isolated from the TNF inhibitor recipients than from controls. Importantly, lower levels of interleukin-2(IL-2) and interferon-gamma (INF-gamma) but not of IL-4 were observed in the lamina propria lymphocyte RNA isolated from the TNF inhibitor recipients. Infiltration and expansion of donor T cells and T-cell activation in the colon appear to be regulated by TNF during murine DBA/2 --> B6D2F1 gut GVHD.
在DBA/2→B6D2F1小鼠结肠移植物抗宿主病（GVHD）模型中，给予编码肿瘤坏死因子（TNF）抑制剂的腺病毒载体可降低结肠炎症的严重程度。本研究评估了TNF阻断对脾脏和结肠T细胞反应的影响。将编码由人55 kDa TNF受体的细胞外结构域与小鼠IgG重链融合而成的人工融合蛋白的cDNA亚克隆到E1a缺陷型腺病毒载体中。将DBA/2 T细胞和骨髓细胞转移到经照射的B6D2F1小鼠体内后，这些小鼠随后接受对照腺病毒或编码TNF抑制剂的腺病毒。分离脾脏和结肠淋巴细胞，用抗H-2b、抗H-2d、抗CD3、抗CD4、抗CD8和抗CD45RB抗体染色，并通过流式细胞术进行分析。还评估了脾脏和结肠淋巴细胞的细胞因子谱。与接受编码TNF抑制剂的腺病毒的小鼠相比，从接受对照腺病毒的小鼠中分离出更多供体来源的结肠T细胞（P = 0.027）。在接受TNF抑制剂的小鼠的结肠中观察到较少的CD4+和CD8+ T细胞，但在脾脏中未观察到。从接受TNF抑制剂的小鼠中分离出的CD4+结肠淋巴细胞中观察到的CD45RBlow（记忆）T细胞比对照组少。重要的是，从接受TNF抑制剂的小鼠中分离出的固有层淋巴细胞RNA中观察到较低水平的白细胞介素-2（IL-2）和干扰素-γ（INF-γ），但未观察到IL-4水平降低。在小鼠DBA/2→B6D2F1肠道GVHD期间，结肠中供体T细胞的浸润和扩增以及T细胞活化似乎受TNF调节。
