Bickerstaff A, Nozaki T, Wang J-J, Pelletier R, Hadley G, Nadasdy G, Nadasdy T, Fairchild R L
Department of Surgery, Transplantation Division, The Ohio State University College of Medicine, Columbus, OH, USA.
Am J Transplant. 2008 Mar;8(3):557-66. doi: 10.1111/j.1600-6143.2007.02125.x.
Increasing detection of acute humoral rejection (AHR) of renal allografts has generated the need for appropriate animal models to investigate underlying mechanisms. Murine recipients lacking the chemokine receptor CCR5 reject cardiac allografts with marked C3d deposition in the parenchymal capillaries and high serum donor-reactive antibody titers, features consistent with AHR. The rejection of MHC-mismatched renal allografts from A/J (H-2(a)) donors by B6.CCR5(-/-) (H-2(b)) recipients was investigated. A/J renal allografts survived longer than 100 days in wild-type C57BL/6 recipients with normal blood creatinine levels (28 +/- 7 micromol/L). All CCR5(-/-) recipients rejected renal allografts within 21 days posttransplant (mean 13.3 +/- 4 days) with elevated creatinine (90 +/- 31 micromol/L). The rejected allografts had neutrophil and macrophage margination and diffuse C3d deposition in peritubular capillaries, interstitial hemorrhage and edema, and glomerular fibrin deposition. Circulating donor-reactive antibody titers were 40-fold higher in B6.CCR5(-/-) versus wild-type recipients. Depletion of recipient CD8 T cells did not circumvent rejection of the renal allografts by CCR5-deficient recipients. In contrast, microMT(-/-)/CCR5(-/-) recipients, incapable of producing antibody, did not reject most renal allografts. Collectively, these results indicate the rapid rejection of renal allografts in CCR5(-/-) recipients with many histopathologic features observed during AHR of human renal allografts.
肾移植急性体液排斥反应（AHR）检测的增加，使得需要合适的动物模型来研究其潜在机制。缺乏趋化因子受体CCR5的小鼠受体排斥心脏移植，在实质毛细血管中有明显的C3d沉积且血清供体反应性抗体滴度较高，这些特征与AHR一致。研究了B6.CCR5(-/-)（H-2(b)）受体对来自A/J（H-2(a)）供体的MHC不匹配肾移植的排斥反应。A/J肾移植在野生型C57BL/6受体中存活超过100天，血肌酐水平正常（28±7微摩尔/升）。所有CCR5(-/-)受体在移植后21天内排斥肾移植（平均13.3±4天），肌酐升高（90±31微摩尔/升）。被排斥的移植肾有中性粒细胞和巨噬细胞边缘化，肾小管周围毛细血管有弥漫性C3d沉积、间质出血和水肿，以及肾小球纤维蛋白沉积。B6.CCR5(-/-)受体的循环供体反应性抗体滴度比野生型受体高40倍。受体CD8 T细胞的清除并不能避免CCR5缺陷受体对肾移植的排斥。相比之下，不能产生抗体的microMT(-/-)/CCR5(-/-)受体并未排斥大多数肾移植。总体而言，这些结果表明CCR5(-/-)受体对肾移植的快速排斥，伴有许多在人类肾移植AHR期间观察到的组织病理学特征。
