Characterization of OX40+ T cells detected in patients with GVHD after hematopoietic stem cell transplantation

我们研究了OX 40/OX 40 L在GVHD中的作用，GVHD被认为是供体来源的T细胞对受体细胞的同种异体反应性免疫应答，我们检测了干细胞移植后100天患者外周血T细胞上OX 40的表达。慢性c型GVHD患者的OX 40 ^+ CD 4 ^+和OX 40 ^+ CD 8 ^+ T细胞百分比均显著高于无慢性c型GVHD患者。系列分析显示，OX 40 ^+ CD 4 ^+ T细胞在cGVHD发病前和发病时升高，与治疗反应密切相关。这些结果表明，连续测量OX 40 ^+ T细胞可用于预测cGVHD的发作以及治疗反应，并提出了OX 40/gp 34系统参与cGVHD发病机制的可能性（Blood 98：3162，2001）。为了更详细地确定OX 40/OX 40 L系统在同种异体反应性中的作用，我们检测了抗OX 40 L mAb对CD 4 ^+ T细胞对同种异体单核细胞来源的DC的增殖反应的影响。我们观察到OX 40的表达依赖于CD 28信号，抗OX 40 L mAb显著抑制了CD 4 ^+ T细胞对同种异体DC甚至分选的OX 40 L ^- DC的增殖反应，表明OX 40/OX 40 L系统在同种异体T细胞免疫应答中起着至关重要的作用（Immunology，109：226-231，2003）。我们发现，OX 40信号传导诱导血管内皮细胞在mRNA和蛋白质水平上产生RANTES，这是我们在用cDNA阵列筛选时首次鉴定的（Immunol. Lett. 84：1，2002）。既然CCR 5 ^+ T细胞被认为是GVHD的启动细胞（Nature Immunol.4：154，2003），这一发现可能与病理生理学有关。

We studied the role of the OX40/OX40L in GVHD that is though to be ascribed to alloreactive immune response of donor-derive T cells to recipient cells.We examined the expression of OX40 on peripheral blood T cells of post-stem cell transplantation patients after day 100. The percentages of both OX40^+CD4^+ and OX40^+CD8^+ T cells were significantly higher in patients with chronic c GVHD than those without. Serial analyses showed that OX40^+CD4^+ T cells elevated before the onset of cGVHD and at the onset closely correlated with the therapeutic response. These results indicated that serial measurement of OX40^+ T cells is useful for predicting the onset as well as therapeutic response of cGVHD and raised a possibility that the OX40/gp34 system is involved in the pathogenesis of cGVHD (Blood 98:3162, 2001). To define the role of the OX40/OX40L system in alloreactivity in more detail, we examined the effect of anti-OX40L mAb on proliferative response of CD4^+ T cells to allogeneic monocyte-derived DCs. We observed that expression of OX40 was dependent on CD28 signals and anti-OX40L mAb markedly inhibited proliferative response of CD4^+ T cells to allogeneic DC and even to sorted OX40L^- DC, indicating that the OX40/OX40L system plays a crucial role in allogeneic T cell immune response (Immunology, 109:226-231, 2003). We found that OX40 signaling induces production of RANTES at both mRNA and protein levels by vascular endothelial cells, which we first identified in screening with cDNA array (Immunol. Lett. 84:1, 2002). Now that CCR5^+ T cells are considered to initiate GVHD (Nature Immunol. 4:154, 2003), this finding may be of pathophysiological relevance.