Liu Jinqi, Heuer Josef G, Na Songqing, Galbreath Elizabeth, Zhang Tonghai, Yang Derek D, Glasebrook Andrew, Song Ho Yeong
Department of Bio-Research Technologies and Proteins, Eli Lilly, Lilly Corporate Center, MC625, Indianapolis, IN 46285, USA.
J Immunol. 2002 Oct 1;169(7):3993-8. doi: 10.4049/jimmunol.169.7.3993.
DR6 is a recently identified member of the TNFR family. In a previous study, we have shown that DR6 KO mice have enhanced CD4(+) T cell proliferation and Th2 cytokine production. Acute graft-vs-host disease (GVHD) results from the activation and expansion of alloreactive donor T cells following bone marrow transplantation. In this article, we demonstrate that the transfer of donor T cells from DR6 KO mice into allogeneic recipient mice in a parent into an F(1) model of acute GVHD results in a more rapid onset of GVHD with increased severity. Recipients of DR6 KO T cells exhibit earlier systemic symptoms of GVHD, more rapid weight loss, earlier histopathological organ damage in the thymus, spleen, and intestines, and earlier mortality. The rapid onset of GVHD in these mice may be attributable to the enhanced activation and expansion of DR6 KO CD4(+) and CD8(+) T cells. Our findings support the hypothesis that DR6 serves as an important regulatory molecule in T cell immune responses. The identification and use of DR6 ligands and/or agonistic Abs to DR6 may represent useful therapeutics in the treatment of T cell-mediated diseases such as GVHD.
DR6是肿瘤坏死因子受体（TNFR）家族中最近被鉴定出的成员。在之前的一项研究中，我们已经表明，DR6基因敲除（KO）小鼠的CD4(+) T细胞增殖和Th2细胞因子产生增强。急性移植物抗宿主病（GVHD）是骨髓移植后同种异体反应性供体T细胞激活和扩增的结果。在本文中，我们证明，在急性GVHD的亲代到F(1)模型中，将来自DR6 KO小鼠的供体T细胞转移到同种异体受体小鼠中会导致GVHD更快发作且严重程度增加。接受DR6 KO T细胞的受体表现出更早的GVHD全身症状、更快的体重减轻、胸腺、脾脏和肠道中更早的组织病理学器官损伤以及更早的死亡。这些小鼠中GVHD的快速发作可能归因于DR6 KO CD4(+)和CD8(+) T细胞的激活和扩增增强。我们的研究结果支持以下假设：DR6在T细胞免疫反应中作为一种重要的调节分子。鉴定和使用DR6配体和/或针对DR6的激动性抗体可能是治疗T细胞介导的疾病（如GVHD）的有用疗法。
