Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
J Am Soc Nephrol. 2019 Dec;30(12):2413-2425. doi: 10.1681/ASN.2018111169. Epub 2019 Oct 9.
The mechanisms underlying the effects of prolonged cold-ischemia storage on kidney allografts are poorly understood.
To investigate effects of cold ischemia on donor-reactive immune responses and graft pathology, we used a mouse kidney transplantation model that subjected MHC-mismatched BALB/c kidney allografts to cold-ischemia storage for 0.5 or 6 hours before transplant into C57BL/6 mice.
At day 14 post-transplant, recipients of allografts subjected to 6 versus 0.5 hours of cold-ischemia storage had increased levels of anti-MHC class II (but not class I) donor-specific antibodies, increased donor-reactive T cells, and a significantly higher proportion of transplant glomeruli infiltrated with macrophages. By day 60 post-transplant, allografts with a 6 hour cold-ischemia time developed extensive glomerular injury compared with moderate pathology in allografts with 0.5 hour of cold-ischemia time. Pathology was associated with increased serum levels of anti-class 2 but not anti-class 1 donor-specific antibodies. Recipient B cell depletion abrogated early macrophage recruitment, suggesting augmented donor-specific antibodies, rather than T cells, increase glomerular pathology after prolonged cold ischemia. Lymphocyte sequestration with sphingosine-1-phosphate receptor 1 antagonist FTY720 specifically inhibited anti-MHC class II antibody production and abrogated macrophage infiltration into glomeruli. Adoptive transfer of sera containing anti-donor MHC class II antibodies or mAbs against donor MHC class II restored early glomerular macrophage infiltration in FTY720-treated recipients.
Post-transplant inflammation augments generation of donor-specific antibodies against MHC class II antigens. Resulting MHC class II-reactive donor-specific antibodies are essential mediators of kidney allograft glomerular injury caused by prolonged cold ischemia.
延长冷缺血储存对肾移植物影响的机制尚不清楚。
为了研究冷缺血对供体反应性免疫应答和移植物病理学的影响，我们使用了一种小鼠肾移植模型，该模型使 MHC 错配的 BALB/c 肾移植物在移植到 C57BL/6 小鼠前经历 0.5 或 6 小时的冷缺血储存。
在移植后 14 天，接受 6 小时而非 0.5 小时冷缺血储存的同种异体移植物的受体具有更高水平的抗 MHC Ⅱ类（而非Ⅰ类）供体特异性抗体，更多的供体反应性 T 细胞，以及明显更高比例的移植肾小球浸润巨噬细胞。在移植后 60 天，与 0.5 小时冷缺血时间的同种异体移植物相比，具有 6 小时冷缺血时间的同种异体移植物发生广泛的肾小球损伤。病理学与血清中抗Ⅱ类但不抗Ⅰ类供体特异性抗体水平升高有关。受体 B 细胞耗竭消除了早期巨噬细胞募集，表明延长冷缺血后，增强的供体特异性抗体而不是 T 细胞增加了肾小球病理学。用鞘氨醇-1-磷酸受体 1 拮抗剂 FTY720 隔离淋巴细胞可特异性抑制抗 MHC Ⅱ类抗体的产生并消除巨噬细胞浸润到肾小球中。含有抗供体 MHC Ⅱ类抗体的血清或针对供体 MHC Ⅱ类的 mAbs 的过继转移恢复了 FTY720 处理的受体中的早期肾小球巨噬细胞浸润。
移植后炎症增强了针对 MHC Ⅱ类抗原的供体特异性抗体的产生。由此产生的 MHC Ⅱ类反应性供体特异性抗体是延长冷缺血引起的肾移植肾小球损伤的重要介质。
