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。移植物抗宿主病动物模型已被用于确定肠道移植物抗宿主病的发病机制。肿瘤坏死因子(TNF)/肿瘤坏死因子受体(TNFR)、淋巴毒素β、LTalphabeta2/LTbetaR和LIGH[(来源于淋巴毒素的同源物可诱导表达并与疱疹病毒进入介质结合)]/LTbetaR的相互作用在肠道移植物抗宿主病的发生发展中起重要作用。本研究旨在探讨肿瘤坏死因子超家族在小鼠肠道移植物抗宿主病中的作用机制。在我们的报告中，阻断肿瘤坏死因子可改善肠道移植物抗宿主病。肿瘤坏死因子及其家族成员可能通过促进促炎T辅助细胞1(Th1)细胞因子的产生而影响GVHD介导的肠炎症。我们实验室的数据表明，肿瘤坏死因子/肿瘤坏死因子受体相互作用和光/LTalphabeta2/LTbetaR相互作用可能是非依赖IL-12和IL-18的Th1增强信号。Th1细胞因子水平的升高可能是由于肿瘤坏死因子家族成员的受体与抗原提呈细胞(APC)结合，从而影响IL-12或IL-18的产生，进而诱导致病T细胞产生Th1细胞因子。或者，肿瘤坏死因子受体或肿瘤坏死因子超家族受体的成员可以向T细胞发出信号，直接放大IL-12或IL-18非依赖的Th-1增强信号。这些研究将验证这一假设，即在特定的CD4T细胞介导的GVHD模型中，肿瘤坏死因子/肿瘤坏死因子受体和LTalphabeta2/LIGHT/LTbetaR的相互作用对致病T细胞的直接或间接激活和分化至关重要。这些研究将利用腺病毒转导系统产生嵌合的肿瘤坏死因子抑制物或LTbeta抑制蛋白的内源性合成，该嵌合蛋白由人55 kDa肿瘤坏死因子受体的胞外域(7，8)或融合到小鼠免疫球蛋白重链(Fc)的LTbeta受体(9，10)组成。在其他实验中，光抗体(11)将被用来阻断光/LTbetaR或光/HVEM相互作用。其具体目的是：1)确定肿瘤坏死因子/肿瘤坏死因子受体相互作用对肠道移植物抗宿主病发生发展的影响是否依赖于IL-12或IL-18。2)明确肿瘤坏死因子/TNFR、LIGH/HVEM、LIGH/LTalphabeta2/LTbetaR相互作用在肠道移植物抗宿主病(GVHD)体内反应发生中的作用；3)确定LIGH/HVEM或LIGH/LTalphabeta2/LTbetaR相互作用在肠道GVHD发生中的作用是否依赖IL-12或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.