Wall D A, Sheehan K C
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110.
Transplantation. 1994 Jan;57(2):273-9. doi: 10.1097/00007890-199401001-00021.
The role of TNF in the expression of GVHD and GVHD-related immunodeficiency was studied in a well-established murine GVHD model of bone marrow transplantation across minor histocompatibility barriers (B10.BR-->GBA/J) both in vitro and in vivo. Splenocytes from animals with GVHD profoundly inhibited the proliferation of normal spleen cells in response to a wide range of stimuli in an MHC-nonrestricted fashion. Neutralizing mAbs to TNF reversed the ability of splenocytes from animals with GVHD to suppress the proliferation of normal splenocytes stimulated by the mitogen concanavalin A. Addition of rTNF enhanced the degree of suppression. This reversal was similar to that previously reported for IFN gamma and leucine methyl ester treatment of the GVHD populations. All three components are necessary for suppression to occur because addition of rTNF to cultures in which suppression had been reversed by anti-IFN gamma or leucine methyl ester treatment did not reconstitute suppression. Neutralization of endogenous TNF production in vivo resulted in an amelioration of clinical GVHD, but neutralization of endogenous IFN gamma resulted in a more severe course. However, in vivo neutralization of either TNF or IFN gamma post-BMT resulted in a decreased ability of splenocytes from animals with GVHD to suppress mitogen responses but did not affect the generation of the suppressor cell population. These findings support multiple roles for TNF and IFN gamma in the pathophysiology of GVHD, including terminal cellular differentiation and/or regulation of effector cell function.
在一个成熟的跨次要组织相容性屏障（B10.BR→GBA/J）的小鼠骨髓移植移植物抗宿主病（GVHD）模型中，在体外和体内研究了肿瘤坏死因子（TNF）在GVHD表达及与GVHD相关的免疫缺陷中的作用。患有GVHD的动物的脾细胞以MHC非限制性方式，显著抑制正常脾细胞对多种刺激的增殖反应。针对TNF的中和性单克隆抗体可逆转患有GVHD的动物的脾细胞抑制由促细胞分裂剂刀豆球蛋白A刺激的正常脾细胞增殖的能力。添加重组TNF（rTNF）可增强抑制程度。这种逆转类似于先前报道的用干扰素γ（IFNγ）和亮氨酸甲酯处理GVHD群体的情况。所有这三种成分都是抑制发生所必需的，因为在已通过抗IFNγ或亮氨酸甲酯处理逆转抑制作用的培养物中添加rTNF并不能恢复抑制作用。体内内源性TNF产生的中和导致临床GVHD的改善，但内源性IFNγ的中和导致病程更严重。然而，骨髓移植后体内对TNF或IFNγ的中和导致患有GVHD的动物的脾细胞抑制促细胞分裂剂反应的能力降低，但不影响抑制性细胞群体的产生。这些发现支持TNF和IFNγ在GVHD病理生理学中的多种作用，包括终末细胞分化和/或效应细胞功能的调节。
