The role of TNF receptor family in intestinal GVHD

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）、淋巴毒素β、ltalphabet2 /LTbeta受体（LTbetaR）和LIGHT[(来源于淋巴毒素的同源物，显示可诱导表达并结合HVEM（疱疹病毒进入介质）]/LTbetaR相互作用似乎在肠道GVHD的发展中很重要。拟议研究的目的是确定TNF超家族对小鼠肠道GVHD的影响机制。在我们的报告中，TNF阻断可改善肠道GVHD。TNF及其家族成员似乎通过增加促炎T辅助1 （Th1）细胞因子的产生来影响GVHD介导的肠道炎症。我们实验室的数据表明TNF/TNFR相互作用和LIGHT/LTalphabeta2/LTbetaR相互作用可能作为IL-12和IL-18无关的Th1增强信号。由于TNF家族成员的受体与抗原呈递细胞（APC）结合，从而影响IL-12或IL-18的产生，进而诱导致病性T细胞产生Th1细胞因子，Th1细胞因子水平可能会升高。或者，TNF受体或TNF超家族受体成员可向T细胞发出信号，直接扩增IL-12或IL-18无关的Th-1增强信号。拟议的研究将验证TNF/TNFR和ltalphabet2 /LIGHT/LTbetaR相互作用对于CD4+ T细胞介导的GVHD特定模型中致病性T细胞的直接或间接激活和分化至关重要的假设。这些研究将利用腺病毒转导系统，产生内源性合成嵌合TNF抑制剂或ltβ抑制剂蛋白，包括人类55 kDa TNF受体的细胞外结构域（7,8）或融合到小鼠免疫球蛋白重链（Fc）的ltβ受体（9,10）。在其他实验中，LIGHT抗体（11）将用于阻断LIGHT/LTbetaR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发展的影响是依赖于IL-12还是IL-18。2)明确TNF/TNFR、LIGHT/HVEM、LIGHT/LTalphabeta2/LTbetaR相互作用在肠道GVHD体内反应发展中的作用；3)明确LIGHT/HVEM或LIGHT/LTalphabeta2/LTbetaR相互作用在肠道GVHD发展中的作用是依赖于IL-12还是IL-18。

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.