Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease
Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease
复制标题
DOI：
10.1182/blood-2006-08-042853
复制
发表时间：
2007-02-15
期刊：
影响因子：
20.3
通讯作者：
Teshima, Takanori
中科院分区：
文献类型：
--
作者：
Sakoda, Yukimi;Hashimoto, Daigo;Teshima, Takanori
慢性移植物抗宿主病（GVHD）是同种异体骨髓移植（BMT）后不良长期预后的最常见原因，但慢性移植物抗宿主病的病理生理机制仍然知之甚少。我们测试了一个假设，即受者的胸腺阴性选择受损将允许致病T细胞的出现，导致慢性GVHD。致命照射的C3H/HeN （H-2(k)）受体用主要组织相容性复合体[MHC] ii类缺陷（H2-Ab1(-/-)） B6 （H-2(b)）小鼠的t细胞缺失骨髓细胞重建。这些小鼠的疾病表现出人类慢性GVHD的所有临床和组织病理学特征。胸腺切除术预防慢性GVHD，从而证实了胸腺的因果关系。从慢性GVHD小鼠中分离的CD4(+) T细胞主要是供体反应性的，在b6来源的抗原呈递细胞存在下，这些小鼠产生的CD4(+) T细胞过继性转移引起C3H/HeN小鼠的慢性GVHD。我们的研究结果首次证明，逃避阴性胸腺选择的T细胞可能在异基因BMT后引起慢性GVHD。这些结果还表明，供体T细胞的自我反应性在慢性GVHD中起作用，胸腺功能的改善可能具有减少慢性GVHD的潜力。（Blood. 2007;109:1756-1764） (c) 2007年由美国血液学会出版。
Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2(k)) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1(-/-)) B6 (H-2(b)) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4(+) T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4(+) T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD. (Blood. 2007;109:1756-1764) (c) 2007 by The American Society of Hematology.