Graubert T A, Russell J H, Ley T J
Department of Internal Medicine and Genetics, Washington University Medical School, St Louis, MO 63110, USA.
Blood. 1996 Feb 15;87(4):1232-7.
A complete molecular description of the syndromes of graft-versus-host disease (GVHD) and graft rejection could have a significant impact on clinical bone marrow transplantation. Recent in vitro experiments (Heusel et al, Cell 76:977, 1994 and Shresta et al, Proc Natl Acad Sci USA 92:5679, 1995) have shown that the putative mediators of these two syndromes, cytotoxic lymphocytes (CTL) and natural killer (NK) cells, respectively, initiate a program of cell death (apoptosis) in susceptible target tissues in a manner critically dependent on the serine protease Granzyme B (gzm B). In the present study, we have analyzed the phenotype of gzm B-deficient mice using experimental transplant models designed to isolate their CD8+ CTL, CD4+ CTL, and NK compartments. We found a significant impairment in class I-dependent GVHD mediated by gzm B -/- CD8+ CTL, whereas class II-dependent GVHD was not altered using gzm B -/- CD4+ effectors. In a hybrid resistance model, gzm B -/- hosts rejected haplo-identical marrow grafts as efficiently as did their wild-type littermates. This result is surprising in light of a severe defect in the ability of gzm B -/- NK cells to induce apoptosis in susceptible targets in vitro. These in vivo data define significant role for gzm B in cytotoxicity mediated by CD8+ CTL, but not by CD4+ CTL. Furthermore, these results do not support a model of hybrid resistance in which NK cells play a pivotal role.
移植物抗宿主病（GVHD）和移植排斥综合征的完整分子描述可能会对临床骨髓移植产生重大影响。最近的体外实验（Heusel等人，《细胞》76:977，1994年；Shresta等人，《美国国家科学院院刊》92:5679，1995年）表明，这两种综合征的假定介质，即细胞毒性淋巴细胞（CTL）和自然杀伤（NK）细胞，分别以严重依赖丝氨酸蛋白酶颗粒酶B（gzm B）的方式在易感靶组织中启动细胞死亡程序（凋亡）。在本研究中，我们使用旨在分离其CD8 + CTL、CD4 + CTL和NK区室的实验移植模型，分析了gzm B缺陷小鼠的表型。我们发现，由gzm B -/- CD8 + CTL介导的I类依赖性GVHD有显著损伤，而使用gzm B -/- CD4 +效应细胞时，II类依赖性GVHD没有改变。在混合抗性模型中，gzm B -/-宿主排斥单倍体相同骨髓移植物的效率与它们的野生型同窝小鼠相同。鉴于gzm B -/- NK细胞在体外诱导易感靶细胞凋亡的能力存在严重缺陷，这一结果令人惊讶。这些体内数据确定了gzm B在由CD8 + CTL介导而非CD4 + CTL介导的细胞毒性中的重要作用。此外，这些结果不支持NK细胞起关键作用的混合抗性模型。
