Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease
Recipient NOD2/CARD15 status affects cellular infiltrates in human intestinal graft-versus-host disease
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DOI：
10.1111/j.1365-2249.2009.04049.x
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发表时间：
2010-01-01
影响因子：
4.6
通讯作者：
Holler, E.
中科院分区：
文献类型：
--
作者：
Landfried, K.;Bataille, F.;Holler, E.
p>核苷酸结合寡聚化结构域2/caspase募集结构域15 （NOD2/CARD15）多态性已被确定为同种异体干细胞移植后克罗恩病和移植物抗宿主病（GVHD）的危险因素。然而，这些先天免疫受体在胃肠道GVHD病理生理中的作用仍不明确。本文分析了58例首次出现肠道症状患者的胃肠道活检中GVHD的免疫组织学特征。观察到的变化与伴随的危险因素和病原体识别受体基因NOD2/CARD15的多态性存在相关。肠道GVHD与CD4 T细胞浸润的阶段性减少和固有层CD8 T细胞的增加有关；CD8浸润与细胞凋亡程度及上皮细胞连续增殖有关。受体中NOD2/CARD15变异的存在与CD4 T细胞的显著损失相关：在半定量分析中，野生型NOD2/CARD15患者的中位CD4评分为1中心点1（范围3），而变异患者的中位CD4评分仅为0中心点4（范围2）（P = 0中心点002）。在多变量分析中，这一观察结果与GVHD的严重程度无关，也不能用叉头盒P3+ T细胞的缺失来解释。我们的研究结果表明，肠道GVHD中保护性CD4 T细胞的损失由于NOD2/CARD15变体的存在而进一步增强。我们的研究可能有助于在未来确定更多的选择性治疗策略。
P>Nucleotide-binding oligomerization domain 2/caspase recruitment domain 15 (NOD2/CARD15) polymorphisms have been identified as risk factors of both Crohn's disease and graft-versus-host disease (GVHD) following allogeneic stem cell transplantation. However, the role of these receptors of innate immunity in the pathophysiology of gastrointestinal GVHD is still poorly defined. Immunohistological features of intestinal GVHD were analysed in gastrointestinal biopsies from 58 patients obtained at the time of first onset of intestinal symptoms. The observed changes were correlated with concomitant risk factors and the presence of polymorphisms within the pathogen recognition receptor gene NOD2/CARD15. Intestinal GVHD was associated with a stage-dependent decrease in CD4 T cell infiltrates and an increase in CD8 T cells in the lamina propria; CD8 infiltrates correlated with extent of apoptosis and consecutive epithelial proliferation. The presence of NOD2/CARD15 variants in the recipient was associated with a significant loss of CD4 T cells: in a semiquantitative analysis, the median CD4 score for patients with wild-type NOD2/CARD15 was 1 center dot 1 (range 3), but only 0 center dot 4 (range 2) for patients with variants (P = 0 center dot 002). This observation was independent from severity of GVHD in multivariate analyses and could not be explained by the loss of forkhead box P3+ T cells. Our results suggest a loss of protective CD4 T cells in intestinal GVHD which is enhanced further by the presence of NOD2/CARD15 variants. Our study might help to identify more selective therapeutic strategies in the future.