The role of TNF receptor family in intestinal GVHD

TNF受体家族在肠道GVHD中的作用

• 批准号: 6603568
• 负责人: GERI R BROWN
• 金额: $ 23.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603568
• 关键词: MHC class II antigen; antibody; antigen presenting cell; cytokine receptors; disease /disorder model; gastrointestinal disorder; graft versus host disease; helper T lymphocyte; inflammation; interferon gamma; interleukin 12; intermolecular interaction; intestines; laboratory mouse; mixed tissue /cell culture; pathologic process; protein structure function; tumor necrosis factor alpha; tumor necrosis factor beta

Gastrointestinal disease is a major cause of morbidity and mortality in human graft-versus-host disease (GVHD). Animal models of GVHD have been used in determining the pathogenesis of gut GVHD. Tumor necrosis factor (TNF)/TNF receptor (TNFR), lymphotoxin beta, LTalphabeta2/LTbeta receptor (LTbetaR) and LIGHT [(derived from homologous to lymphotoxins shows inducible expression and binds to HVEM (Herpes Virus Entry Mediator)] /LTbetaR interactions appear to be important in the development of gut GVHD. The purpose of the proposed studies is to determine the mechanisms of the effects of the TNF superfamily on murine gut GVHD. In our reports, TNF blockade ameliorates gut GVHD. TNF and its family members appear to influence GVHD mediated intestinal inflammation by augmentation of pro-inflammatory T helper 1 (Th1) cytokine production. Data from our laboratory suggest that TNF/TNFR interactions and LIGHT/LTalphabeta2/LTbetaR interactions may serve as an IL-12 and IL-18 independent Th1 augmentation signal. Enhanced Th1 cytokine levels could occur due to the engagement of TNF family members' receptors on antigen presenting cells (APC's) that affect the production of IL-12 or IL-18 which further induce Th1 cytokine production from pathogenic T cells. Alternatively, TNF receptors or members of TNF superfamily receptors could signal the T cell to directly amplify IL-12 or IL-18 independent Th-1 augmentation signals. The proposed studies will test the hypothesis that TNF/TNFR and LTalphabeta2/LIGHT/LTbetaR interactions are critical for the direct or indirect activation and differentiation of pathogenic T cells in specific models of CD4+ T cell mediated GVHD. These studies will utilize an adenoviral transduction system that generates endogenous synthesis of a chimeric TNF inhibitor or LTbeta inhibitor protein, consisting of the extracellular domain of the human 55 kDa TNF receptor (7,8) or the LTbeta receptor fused to the heavy chain of mouse immunoglobulin (Fc) (9,10). In other experiments, LIGHT antibody (11) will be used to block LIGHT/LTbetaR or LIGHT/HVEM interaction. The specific aims are: 1) Determine whether the effect of TNF/TNFR interactions on the development of intestinal GVHD is IL-12 or IL-18 dependent. 2) Define the role of TNF/TNFR, LIGHT/HVEM, LIGHT/LTalphabeta2/LTbetaR interactions on the development of in vivo responses in gut GVHD and 3) Define whether the role of LIGHT/HVEM or LIGHT/LTalphabeta2/LTbetaR interactions on the development of intestinal GVHD is IL-12 or IL-18 dependent.

胃肠道疾病是人类移植物抗宿主病（GVHD）发病和死亡的主要原因。 GVHD的动物模型已被用于确定肠道GVHD的发病机制。 肿瘤坏死因子（TNF）/TNF受体（TNFR）、光毒素β、LT β 2/LT β受体（LT β R）和LIGHT [（来源于光毒素的同源物，显示可诱导表达并结合HVEM（疱疹病毒进入介体）] /LT β R相互作用似乎在肠道GVHD的发展中是重要的。 本研究的目的是确定TNF超家族对小鼠肠道GVHD的作用机制。 在我们的报告中，TNF阻断改善肠道GVHD。TNF及其家族成员似乎通过增加促炎性T辅助细胞1（Th 1）细胞因子的产生来影响GVHD介导的肠道炎症。 来自我们实验室的数据表明，TNF/TNFR相互作用和LIGHT/LT β 2/LT β R相互作用可能作为IL-12和IL-18独立的Th 1增强信号。 由于TNF家族成员的受体在抗原呈递细胞（APC）上的接合，可能发生Th 1细胞因子水平的增强，所述抗原呈递细胞影响IL-12或IL-18的产生，所述IL-12或IL-18进一步诱导Th 1细胞因子从病原性T细胞产生。 或者，TNF受体或TNF超家族受体的成员可以向T细胞发出信号以直接扩增IL-12或IL-18非依赖性Th-1增强信号。所提出的研究将检验TNF/TNFR和LT β 2/LIGHT/LT β R相互作用对于CD 4 + T细胞介导的GVHD的特定模型中的致病性T细胞的直接或间接活化和分化至关重要的假设。 这些研究将利用腺病毒转导系统，该系统产生嵌合TNF抑制剂或LT β抑制剂蛋白的内源性合成，由人55 kDa TNF受体的胞外结构域（7，8）或与小鼠免疫球蛋白（Fc）重链融合的LT β受体（9，10）组成。 在其他实验中，LIGHT抗体（11）将用于阻断LIGHT/LT β R或LIGHT/HVEM相互作用。 具体目的是：1）确定TNF/TNFR相互作用对肠道GVHD发展的影响是否是IL-12或IL-18依赖的。2)确定TNF/TNFR、LIGHT/HVEM、LIGHT/LTB 2/LTbetaR相互作用对肠GVHD中体内应答的发展的作用，和3）确定LIGHT/HVEM或LIGHT/LTB 2/LTbetaR相互作用对肠GVHD发展的作用是否是IL-12或IL-18依赖性的。