Relevance of the direct pathway of sensitization in corneal transplantation is dictated by the graft bed microenvironment
Relevance of the direct pathway of sensitization in corneal transplantation is dictated by the graft bed microenvironment
复制标题
DOI：
10.4049/jimmunol.173.7.4464
复制
发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Dana, MR
中科院分区：
文献类型：
--
作者：
Huq, S;Liu, Y;Dana, MR
直到最近，角膜移植物被认为完全没有常驻APC，从而产生了同种异体抗原识别仅由间接（宿主APC依赖性）途径介导的原则。最近发现的居民髓样角膜树突状细胞群体，通常是MHC II类-但可以很容易地上调II类表达在炎症导致我们假设，在某些条件下，直接途径的allosensitization成为操作。为了测试这一点，在小鼠的发炎（高风险（HR））或未发炎（低风险（LR））宿主床中进行角膜同种异体移植，并确定通过直接途径激活的宿主T细胞的频率。我们发现，直接致敏的CD 4（+）T细胞在HR中检测到，但在LR中没有检测到，这些细胞在移植后2周显示出明显的Th 1表型。此外，使用MHC II类基因敲除的供体组织导致HR而不是LR同种异体移植物的存活率显著提高。最后，我们发现供体角膜APC表现出高表达的CD 40，CD 80和CD 86共刺激分子时，来自HR，但不是LR移植。这些数据是第一次报告，功能性供体APC依赖的直接反应引起角膜移植宿主时，移植床发炎，并强调移植微环境的相关性，在支配的途径allosensitization。
Corneal grafts were until recently considered entirely devoid of resident APCs, giving rise to the tenet that alloantigen recognition is mediated exclusively by the indirect (host APC-dependent) pathway. The recent discovery of a resident myeloid corneal dendritic cell population that is normally MHC class II- but can readily up-regulate class II expression during inflammation led us to hypothesize that under certain conditions the direct pathway of allosensitization becomes operative. To test this, corneal allotransplants were performed in either inflamed (high-risk (HR)) or uninflamed (low-risk (LR)) host beds in mice, and the frequencies of host T cells activated via the direct pathway were determined. We found that directly primed CD4(+) T cells were detected in the HR but not LR setting, and these cells displayed a clear Th1 phenotype by 2 wk after grafting. Moreover, the use of MHC class II knockout donor tissue led to significantly enhanced survival of HR but not LR allografts. Finally, we show that donor corneal APC demonstrate high expression of CD40, CD80, and CD86 costimulatory molecules when derived from HR but not LR grafts. These data are the first to report that a functional donor APC-dependent direct response is elicited in corneal transplant hosts when the graft bed is inflamed and underscore the relevance of the graft microenvironment in dictating the pathway of allosensitization.