Lorber M I, Wilson J H, Robert M E, Schechner J S, Kirkiles N, Qian H Y, Askenase P W, Tellides G, Pober J S
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8062, USA.
Transplantation. 1999 Mar 27;67(6):897-903. doi: 10.1097/00007890-199903270-00018.
Interspecies differences create important shortcomings in existing animal models used to describe in vivo events responsible for allograft rejection. Alloimmune destruction of human dermal microvessels, histologically consistent with rejection, has been demonstrated in human skin-grafted severe combined immunodeficient (SCID) mice receiving allogeneic human peripheral blood mononuclear cells (PBMC). We have now documented human alloimmune injury in a vascularized, SCID-human arterial transplantation model.
Fresh human artery was used to replace the CB.17 SCID/beige mouse infrarenal aorta. Seven days later, 3x10(8) human PBMC were administered intraperitoneally, and lymphocyte engraftment was considered successful when circulating human CD3+ cells were later identified in peripheral blood.
Forty-six of 49 (94%) mice undergoing transplantation survived, including 14 controls with arterial grafts receiving no PBMC. Twenty-eight of 32 mice demonstrated circulating human CD3+ cells, 14 days after PBMC administration. Animals were killed at 14, 21, or 28 days after receiving allogeneic PBMC, and arteries were recovered for histology and immunohistology. All 14 control mice had patent transplanted grafts with normal vascular histology and no lymphoid infiltration. Damage to transplanted arteries among lymphocyte-engrafted mice was apparent by 14 and 21 days in some animals, whereas 16 of 22 exhibited moderate to severe intimal, medial, and/or adventitial lymphocytic infiltration with intimal expansion by day 28. The infiltrate consisted of HLA-A, -B, -C+, and -DR+, human CD3+ cells, approximately equally distributed as CD4+ and CD8+ subsets. Some infiltrating lymphocytes were cytolytic cells as demonstrated by perforin staining. The endothelium of transplanted human arteries exhibited endothelialitis, and the endothelial cells stained intensely with anti-HLA-A, -B, -C and anti-HLA-DR antibodies. The expanded intima was predominantly smooth muscle cells, staining positively for smooth muscle alpha-actin, HLA-A, -B, -C and HLA-DR. Medial necrosis was not observed.
The results provide evidence of alloimmune-mediated vascular rejection in this human arterial transplantation model.
种间差异使得用于描述同种异体移植排斥反应体内事件的现有动物模型存在重要缺陷。在接受同种异体人外周血单个核细胞（PBMC）的人皮肤移植重症联合免疫缺陷（SCID）小鼠中，已证实人真皮微血管的同种异体免疫破坏在组织学上与排斥反应一致。我们现在已在一个血管化的SCID-人动脉移植模型中记录了人同种异体免疫损伤。
使用新鲜人动脉替换CB.17 SCID/米色小鼠肾下腹主动脉。7天后，腹腔内注射3×10⁸人PBMC，当随后在外周血中鉴定出循环人CD3⁺细胞时，认为淋巴细胞植入成功。
49只接受移植的小鼠中有46只（94%）存活，包括14只接受动脉移植但未接受PBMC的对照小鼠。32只小鼠中有28只在注射PBMC后14天出现循环人CD3⁺细胞。在接受同种异体PBMC后14、21或28天处死动物，回收动脉进行组织学和免疫组织学检查。所有14只对照小鼠的移植移植物通畅，血管组织学正常，无淋巴细胞浸润。淋巴细胞植入小鼠中移植动脉的损伤在14天和21天时在一些动物中明显，而22只中有16只在第28天时表现出中度至重度的内膜、中膜和/或外膜淋巴细胞浸润以及内膜增生。浸润细胞由HLA-A、-B、-C⁺和-DR⁺、人CD3⁺细胞组成，作为CD4⁺和CD8⁺亚群大致均匀分布。如穿孔素染色所示，一些浸润淋巴细胞是细胞溶解细胞。移植人动脉的内皮表现出内皮炎，内皮细胞用抗HLA-A、-B、-C和抗HLA-DR抗体染色强烈。增生的内膜主要是平滑肌细胞，平滑肌α-肌动蛋白、HLA-A、-B、-C和HLA-DR染色呈阳性。未观察到中膜坏死。
结果提供了该人动脉移植模型中同种异体免疫介导的血管排斥反应的证据。
