Interleukin-12 inhibits graft-versus-host disease through an Fas-mediated mechanism associated with alterations in donor T-cell activation and expansion
Interleukin-12 inhibits graft-versus-host disease through an Fas-mediated mechanism associated with alterations in donor T-cell activation and expansion
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DOI：
10.1182/blood.v91.9.3315.3315_3315_3322
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发表时间：
1998-05-01
期刊：
影响因子：
20.3
通讯作者：
Sykes, M
中科院分区：
文献类型：
--
作者：
Dey, BR;Yang, YG;Sykes, M
我们最近提出了一个矛盾的观察结果，即在骨髓移植（BMT）当天单次注射重组鼠白细胞介素-12（IL-12）可抑制接受完全主要组织相容性复合物（MHC）不匹配的骨髓和脾细胞的致死性照射小鼠的移植物抗宿主病（GVHD）。我们现在已经研究了IL-12对急性GVHD的这种作用的机制。在BMT后第4天，与GVHD对照组相比，IL-12处理的小鼠显示脾供体CD 4（+）和CD 8（+）T细胞显著减少。与GVHD对照组相比，IL-12治疗组小鼠脾供体CD 4（+）细胞上早期活化标志物IL-2 R α链（CD 25）和CD 69的表达在早期时间点（BMT后36和72小时）显著更高。然而，与GVHD对照组相比，IL-12保护的小鼠中供体T细胞上CD 25和极晚期抗原-4（VLA-4）表达的GVHD相关增加被大大抑制。在IL-12处理组中，到第4天，宿主反应性T辅助细胞的显著GVHD相关扩增也被完全抑制。与对照组相比，IL-12处理小鼠骨髓移植后第3天至第7天供体CD 4细胞Fas表达增加。此外，IL-12对GVHD的保护能力至少部分依赖于供体细胞表达功能性Fas分子的能力。我们得出结论，在BMT时IL-12处理显著干扰了同种异体反应性供体CD 4（+）T细胞的活化，这些T细胞在急性GVHD的发病机制中起关键作用，我们假设这些扰动最终导致供体T细胞的Fas依赖性凋亡，从而阻碍它们的扩增和促进GVHD的活性。(C)1998年，美国血液学会。
We have recently made the paradoxical observation that a single injection of recombinant murine interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving fully major histocompatability complex (MHC)mismatched bone marrow and spleen cells. We have now examined the mechanism of this effect of IL-12 on acute GVHD, By day 4 post-BMT, IL-12-treated mice showed marked reductions in splenic donor CD4(+) and CD8(+) T cells compared with GVHD controls. Expression of the early activation markers IL-2R alpha chain (CD25) and CD69 on splenic donor CD4(+) cells was considerably higher at early time points (36 and 72 hours post-BMT) in IL-12-treated mice compared with GVHD controls. However, the later, GVHD-associated increase in CD25 and very late antigen-4 (VLA-4) expression on donor T cells was greatly depressed in IL-12-protected mice compared with GVHD controls. The marked GVHD-associated expansion of host-reactive T helper cells by day 4 was also completely inhibited in the IL-12-treated group. Expression of Fas was increased on donor CD4 cells of IL-12-treated mice compared with those of controls on days 3 through 7 post-BMT. Furthermore, the ability of IL-12 to protect against GVHD was at least partially dependent on the ability of donor cells to express functional Fas molecules, We conclude that IL-12 treatment at the time of BMT markedly perturbs the activation of alloreactive donor CD4(+) T cells that play a critical role in the pathogenesis of acute GVHD, We hypothesize that these perturbations culminate in Fas-dependent apoptosis of donor T cells, thus impeding their expansion and their GVHD-promoting activity. (C) 1998 by The American Society of Hematology.