The role of monocytes in the regulation of GVHD after allogeneic stem cell transplantation.

尽管粒细胞集落刺激因子(G-CSF)动员的外周血单核细胞(G-PBMC)移植的T细胞数量至少是标准骨髓移植的10倍，但急性移植物抗宿主病(AGVHD)的发生率和严重程度并不高于异基因骨髓。我们发现，共刺激分子CD28应答复合体在CD4+细胞中的诱导似乎被G-PBMC中CD14+细胞的存在所抑制。最近的研究表明，NK细胞上的抑制性自然杀伤细胞受体(NKRs)通过与MHC-I类分子结合来负向调节NK细胞和T细胞的功能。CD94/NKG2异源二聚体是人类白细胞抗原E非经典分子的受体。我们发现cGVHD患者T细胞表面CD94/NKG2A的表达在常规免疫抑制治疗效果良好的cGVHD患者中明显高于cGVHD治疗效果差的患者。此外，我们还报道了混合淋巴细胞培养(MLC)后G-PBMC中CD8+T细胞表面CD94/NKG2A的表达增加。然而，CD14缺失的G-PBMC并不增加CD94/NKG2A的表达。将纯化的CD14+细胞加入CD14缺失的G-PBMC中，以剂量依赖的方式诱导CD94/NKG2A的表达，然而，这种促进CD94/NKG2A表达的作用被反应细胞和CD14+细胞之间的膜所抑制。因此，G-PBMC中的CD14+细胞诱导CD8+T细胞表达CD94/NKG2A，进而下调同种异体反应。因此，抑制T细胞上NKR的表达在调节同种异体反应中具有重要作用。

Although granulocyte colony-stimulating factor (G-CSF)-mobillized peripheral blood mononuclear cells (G-PBMC) grafts contain at least ten times more T cells than standard bone marrow grafts, the incidence and severity of acute graft-versus-host disease (aGVHD) is not higher than that observed with allogeneic marrow. We have shown that the induction of constimulatory molecule CD28 responsive complex in CD4+ cells appears to be suppressed by the presence of CD14+ cells in the G-PBMCIt has recently been shown that inhibitory natural killer cell receptors (NKRs) on NK cells negatively regulate NK cell and also T cell functions through their binding to MHC class I molecules. A CD94/NKG2 heterodimer serves as a receptor for HLA-E non-classical HLA-I molecules. We showed the expression of CD94/NKG2A on T cells was higher in cGVHD patients with good response to conventional immunosuppressive therapy than in cGVHD patients with poor response. Also, we reported the increased expression of CD94/NKG2A on CD8+ T cells in G-PBMC after mixed lymphocyte culture (MLC). However, CD94/NKG2A expression did not increase when CD14-depleted G-PBMC was used. The addition of purified CD14+ cells to CD14-depleted G-PBMC induced CD94/NKG2A expression in a dose-dependent fashion, however, this enhancing effect of purified CD14+ cells on CD94/NKG2A expression was inhibited by the presence of a membrane between responder cells and CD14+ cells. Therefor, CD14+ cells in G-PBMC induce CD94/NKG2A expression on CD8+ T cells, which in turn appear to down-regulate alloresponses. Therefore, inhibitory NKR expression on T cells has an important role in the regulation of alloresponse.