Leveque-El Mouttie Lucie, Koyama Motoko, Le Texier Laetitia, Markey Kate A, Cheong Melody, Kuns Rachel D, Lineburg Katie E, Teal Bianca E, Alexander Kylie A, Clouston Andrew D, Blazar Bruce R, Hill Geoffrey R, MacDonald Kelli P A
Antigen Presentation and Immunoregulation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia; The University of Queensland, Brisbane, Australia;
Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia;
Blood. 2016 Aug 11;128(6):794-804. doi: 10.1182/blood-2015-11-680876. Epub 2016 Jun 23.
Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.
慢性移植物抗宿主病（cGVHD）是异基因骨髓移植（BMT）后晚期死亡的主要原因，其特征为组织纤维化，表现为硬皮病和闭塞性细支气管炎。急性移植物抗宿主病（aGVHD）的发生是后续cGVHD的有力临床预测指标，提示aGVHD可能引发了导致cGVHD的免疫途径。在前期经历轻度aGVHD后发生硬皮病样cGVHD的临床前模型中，我们发现骨髓移植后早期供体树突状细胞（DC）的主要组织相容性复合体（MHC）II类分子内的抗原呈递明显受损。这与调节性T细胞（Treg）稳态失衡和cGVHD有关。供体DC特异性缺失MHC II类分子可模拟这种Treg缺陷和cGVHD。此外，骨髓移植后特异性清除供体Treg也可诱导cGVHD，而Treg的过继转移则可改善cGVHD。这些数据表明，cGVHD中所见的Treg稳态缺陷是一个致病损伤，且位于由aGVHD诱导的MHC II类分子内抗原呈递缺陷的下游。
