Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cell sin allograft tolerance by LF15-0195 treatment
Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cell sin allograft tolerance by LF15-0195 treatment
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DOI：
10.4049/jimmunol.168.10.5058
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发表时间：
2002-05-15
影响因子：
4.4
通讯作者：
Cuturi, MC
中科院分区：
文献类型：
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作者：
Chiffoleau, E;Bériou, G;Cuturi, MC
LF15-0195，一种脱氧精氨酸类似物，治疗20天，在大鼠完全MHC不相合的同种异体心脏移植模型中诱导同种异体移植耐受。长期同种异体移植物的细胞浸润率很低，没有慢性排斥反应的迹象。来自耐受LF15-0195的受者的CD4+脾T细胞在体外能够抑制同种异体的CD4(+)T细胞的增殖，并将耐受性转移给第二同基因的受者，表现出由调节细胞的优势抑制。经LF15-0195免疫耐受的受者胸腺和脾中的CD4(+)CD25(+)T细胞百分率显著升高。供体APC体外直接刺激显示，CD4(+)调节性T细胞弱增殖，低水平表达ITN-γ、IL-10和IL-2。去除CD4(+)CD25(+)细胞可增加胸腺细胞产生IL-2，但不能增加脾细胞产生IL-2。此外，耐受性可以与脾和胸腺的CD4(+)CD25(+)细胞转移，但也可以在50%的脾CD4+CD25-细胞的病例中转移，这表明CD25可以作为胸腺调节细胞的标志，但在外周不能。此外，我们还提供了供体APC需要诱导耐受和扩增调节性CD4(+)T细胞的证据。这项研究表明，LF15-0195治疗诱导供者APC扩增存在于中央和外周隔室的强大的调节性CD4(+)CD25(+/-)T细胞。
A 20-day treatment with LF15-0195, a deoxyspergualine analogue, induced allograft tolerance in a fully; MHC-mismatched heart allograft model in the rat. Long-term allografts displayed minimal cell infiltration with no signs of chronic rejection. CD4+ spleen T cells; from tolerant LF15-0195-treated recipients were able to suppress in vitro proliferation of allogeneic CD4(+) T cells and to transfer tolerance to second syngeneic recipients, demonstrating dominant suppression by regulatory cells. A significant increase in the percentage of CD4(+)CD25(+) T cells was observed in the thymus and spleen from tolerant LF15-0195-treated recipient. In vitro direct stimulation with donor APCs demonstrated that CD4(+) regulatory T cells proliferated weakly and expressed low levels of ITN-gamma, IL-10, and IL-2. CD4(+)CD25(+) cell depletion increased IL-2 production by CD4(+)CD25(-) thymic cells, but not splenic cells. Moreover, tolerance was transferable with splenic and thymic CD4(+)CD25(+) cells, but also in 50% of cases with splenic CD4+CD25- cells, demonstrating that CD25 can be a marker for regulatory cells in the thymus, but not in the periphery. In addition, we presented evidences that donor APCs were required to induce tolerance and to expand regulatory CD4(+) T cells. This study demonstrates that LF15-0195 treatment induces donor APCs to expand powerful regulatory CD4(+) CD25(+/-) T cells present in both the central and peripheral compartments.