Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease
Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease
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DOI：
10.1182/blood-2008-08-175448
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发表时间：
2009-03-05
期刊：
影响因子：
20.3
通讯作者：
Drobyski, William R.
中科院分区：
文献类型：
--
作者：
Das, Rupali;Chen, Xiao;Drobyski, William R.
在移植物抗宿主病（GVHD）期间，调节方案与同种异体反应性供体T细胞联合引起的胃肠道损伤在该疾病的发病机制中起关键作用。在这项研究中，我们发现供体抗原呈递细胞（APCs）分泌白素-23 （IL-23）是诱导结肠GVHD的关键事件，将调节方案诱导的粘膜损伤和脂多糖（LPS）易位与随后的促炎细胞因子产生和GVHD相关的病理损伤联系起来。在供体apc来源的IL-23分泌缺失的情况下，病理损伤有选择性地显著减少，结肠微环境中LPS和促炎细胞因子的产生也显著减少。IL-23的下游促炎作用依赖于供体来源的干扰素γ (ifn - γ)的分泌，但不依赖于供体IL-17的产生。这些发现定义了IL-23在GVHD病理生理中的新的器官特异性作用，并证明IL-23可以在全身性炎症疾病的背景下指导组织特异性病理。此外，这些研究还确定IL-23是预防这种危及生命的疾病的潜在治疗靶点。（血液杂志，2009;113:2352-2362）
Damage to the gastrointestinal tract during graft-versus-host disease (GVHD) from the conditioning regimen in conjunction with alloreactive donor T cells plays a pivotal role in the pathogenesis of this disease. In this study, we have identified secretion of interleukin-23 (IL-23) by donor antigen-presenting cells (APCs) as a critical event in the induction of GVHD of the colon linking conditioning regimen-induced mucosal injury and lipopolysaccharide (LPS) translocation to subsequent proinflammatory cytokine production and GVHD-associated pathologic damage. In the absence of donor APC-derived IL-23 secretion, there is a selective and profound reduction in pathologic damage as well as a marked reduction in LPS and proinflammatory cytokine production in the colon microenvironment. The downstream proinflammatory effects of IL-23 are dependent upon donor-derived secretion of interferon-gamma (IFN-gamma), but are independent of donor IL-17 production. These findings define a novel organ-specific role for IL-23 in the pathophysiology of GVHD and demonstrate that IL-23 can direct tissue-specific pathology within the context of a systemic inflammatory disorder. Furthermore, these studies also identify IL-23 as a potential therapeutic target for the prevention of this life-threatening disorder. (Blood. 2009; 113: 2352-2362)