Rao Arun R, Quinones Marlon P, Garavito Edgar, Kalkonde Yogeshwar, Jimenez Fabio, Gibbons Caroline, Perez Jennifer, Melby Peter, Kuziel William, Reddick Robert L, Ahuja Sunil K, Ahuja Seema S
South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78284, USA.
J Immunol. 2003 Nov 1;171(9):4875-85. doi: 10.4049/jimmunol.171.9.4875.
The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6-->bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4(+) T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-gamma-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4(+) T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2(-/-) CD4(+) T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4(+) T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2(-/-) splenocyte-->bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.
影响移植物抗宿主病（GVHD）的细胞和分子决定因素的完整组成尚不清楚。我们利用一个成熟的GVHD小鼠模型（B6→bm12小鼠），试图阐明供体非T细胞区室及其内部分子决定因素在GVHD发病机制中的作用。在这个模型中，野生型（wt）非T细胞以剂量依赖的方式抑制了纯化的B6野生型CD4(+) T细胞诱导急性GVHD的作用。矛盾的是，与移植了B6wt未分离脾细胞的bm12小鼠中观察到的慢性GVHD表型不同，接受B6ccr2基因敲除未分离脾细胞的bm12受体发生了急性GVHD，并死于IFN-γ介导的骨髓再生障碍。这种从慢性GVHD到急性GVHD的转变与活化CD4(+) T细胞对靶器官浸润增加以及Th1/Th2细胞因子、趋化因子和抗凋亡因子bfl1的表达增强有关。在体外，未分离脾细胞中的ccr2(-/-) CD4(+) T细胞比B6wt CD4(+) T细胞经历的活化诱导细胞死亡明显更少，这为B6ccr2(-/-)脾细胞→bm12小鼠靶器官中活化T细胞数量增加提供了另一个潜在的机制基础，同时也与bfl1表达增强有关。总的来说，这些发现具有重要的临床意义，因为它们表明供体非T细胞区室是GVHD的关键调节因子，并提示该细胞区室中ccr2的表达可能是活化诱导细胞死亡和GVHD发病机制的重要分子决定因素。
