Lin C M, Plenter R J, Coulombe M, Gill R G
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO.
Department of Surgery, University of Colorado, Aurora, CO.
Am J Transplant. 2016 Nov;16(11):3121-3130. doi: 10.1111/ajt.13865. Epub 2016 Jul 7.
Natural killer (NK) cells are key components of the innate immune system. In murine cardiac transplant models, donor-specific antibodies (DSA), in concert with NK cells, are sufficient to inflict chronic allograft vasculopathy independently of T and B cells. In this study, we aimed to determine the effector mechanism(s) required by NK cells to trigger chronic allograft vasculopathy during antibody-mediated rejection. Specifically, we tested the relative contribution of the proinflammatory cytokine interferon gamma (IFN-γ) versus the contact-dependent cytotoxic mediators of perforin and the CD95/CD95L (Fas/Fas ligand [FasL]) pathway for triggering these lesions. C3H/HeJ cardiac allografts were transplanted into immune-deficient C57BL/6 rag γc recipients, who also received monoclonal anti-major histocompatibility complex (MHC) class I DSA. The combination of DSA and wild-type NK cell transfer triggered aggressive chronic allograft vasculopathy. However, transfer of IFN-γ-deficient NK cells or host IFN-γ neutralization led to amelioration of these lesions. Use of either perforin-deficient NK cells or CD95 (Fas)-deficient donors alone did not alter development of vasculopathy, but simultaneous disruption of NK cell-derived perforin and allograft Fas expression resulted in prevention of these abnormalities. Therefore, both NK cell IFN-γ production and contact-dependent cytotoxic activity are rate-limiting effector pathways that contribute to this form of antibody-induced chronic allograft vasculopathy.
自然杀伤（NK）细胞是先天性免疫系统的关键组成部分。在小鼠心脏移植模型中，供体特异性抗体（DSA）与NK细胞协同作用，足以独立于T细胞和B细胞引发慢性移植血管病。在本研究中，我们旨在确定NK细胞在抗体介导的排斥反应中引发慢性移植血管病所需的效应机制。具体而言，我们测试了促炎细胞因子干扰素γ（IFN-γ）与穿孔素和CD95/CD95L（Fas/Fas配体 [FasL]）途径的接触依赖性细胞毒性介质在引发这些病变中的相对作用。将C3H/HeJ心脏同种异体移植物移植到免疫缺陷的C57BL/6 rag γc受体中，这些受体还接受了单克隆抗主要组织相容性复合体（MHC）I类DSA。DSA与野生型NK细胞转移的组合引发了侵袭性慢性移植血管病。然而，IFN-γ缺陷型NK细胞的转移或宿主IFN-γ中和导致这些病变得到改善。单独使用穿孔素缺陷型NK细胞或CD95（Fas）缺陷型供体不会改变血管病的发展，但同时破坏NK细胞衍生的穿孔素和同种异体移植物Fas表达可预防这些异常。因此，NK细胞产生IFN-γ和接触依赖性细胞毒性活性都是导致这种形式的抗体诱导的慢性移植血管病的限速效应途径。
