Bone Marrow Transplantation Laboratory, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Medical Genomics Laboratory, Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Immunity. 2019 Nov 19;51(5):885-898.e7. doi: 10.1016/j.immuni.2019.08.011. Epub 2019 Sep 18.
Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.
移植物抗宿主病（GVHD）在胃肠道是同种异体骨髓移植（BMT）后致死的主要决定因素。在这里，我们研究了引发 GVHD 的机制，包括相关的抗原呈递细胞。在稳态时，MHC Ⅱ类分子在回肠的肠上皮细胞（IECs）上表达，但在无菌小鼠的 IECs 上不存在。IEC 特异性敲除 MHC Ⅱ类分子可防止胃肠道致命性 GVHD 的发生。MHC Ⅱ类分子在 MyD88 和 TRIF 缺失的 TLR 衔接子缺失的小鼠的 IECs 上缺失，并且需要固有层淋巴细胞分泌 IFNγ。IFNγ 反应的特征是由髓样细胞分泌的 IL-12 驱动。抗生素介导的微生物群耗竭抑制了回肠巨噬细胞中 IL-12/23p40 的产生。IL-12/23p40 中和可防止 IEC 上 MHC Ⅱ类分子的上调，并防止胃肠道致命性 GVHD 的发生。因此，回肠 IEC 上 MHC Ⅱ类分子的表达引发致命性 GVHD，而 IL-12/23p40 的阻断可能代表一种易于转化的治疗策略。
