Orosz C G, Huang E H, Bergese S D, Sedmak D D, Birmingham D J, Ohye R G, VanBuskirk A M
Department of Surgery, Ohio State University College of Medicine, Columbus, USA.
J Heart Lung Transplant. 1997 Sep;16(9):889-904.
We treated C57BL/6 mouse recipients of DBA/2 cardiac allografts with anti-CD4 monoclonal antibodies (mAb) or anti-vascular cell adhesion molecule 1 mAb to promote long-term allograft survival and subjected both the recipient animals and the long-surviving allografts to a battery of histologic and immunologic tests. The results were similar regardless of the mAb used for antirejection therapy. At all tested times after transplantation, the allografts displayed histologic evidence of ongoing microvascular endothelial activation and interstitial leukocytic infiltration. Reverse transcription polymerase chain reaction analyses revealed continuous intragraft expression of messenger RNA for interleukin 1, interleukin 2, interleukin 4, interleukin 6, tumor necrosis factor, interferon gamma, and transforming growth factor beta. All grafts had histologic evidence of ongoing vascular and parenchymal tissue remodeling, including interstitial fibrosis and vascular neointimal hyperplasia. The graft recipients retained limiting dilution analysis--detectable, donor-reactive cytolytic T lymphocyte, and helper T lymphocyte in their spleens and produced high liters of donor-reactive alloantibodies. Variable amounts of allogeneic microchimerism were detectable in some, but not all of the long-surviving graft recipients. In general, these observations indicate that (1) a similar immune status is achieved in long-surviving allografts and their recipients when either anti-CD4 mAb or anti-vascular cell adhesion molecule-1 mAb was used for antirejection therapy, in spite of the major differences in lineage and distribution of cells targeted by these two mAbs, (2) this immune status is characterized by continuous, long-term inflammatory and immune processes very similar to those observed during acute allograft rejection, and (3) in spite of these processes the allografts continue to function, although they invariably develop a chronic rejection-like histopathologic condition that may ultimately limit graft function. In this regard, the recipients of long-surviving allografts do not seem to be tolerant of their graft alloantigens.
我们用抗CD4单克隆抗体（mAb）或抗血管细胞黏附分子1单克隆抗体治疗接受DBA/2心脏同种异体移植的C57BL/6小鼠受体，以促进同种异体移植的长期存活，并对受体动物和长期存活的同种异体移植进行了一系列组织学和免疫学检测。无论用于抗排斥治疗的单克隆抗体如何，结果都是相似的。在移植后的所有测试时间，同种异体移植均显示出正在进行的微血管内皮激活和间质白细胞浸润的组织学证据。逆转录聚合酶链反应分析显示，移植物内白细胞介素1、白细胞介素2、白细胞介素4、白细胞介素6、肿瘤坏死因子、干扰素γ和转化生长因子β的信使核糖核酸持续表达。所有移植物都有正在进行的血管和实质组织重塑的组织学证据，包括间质纤维化和血管内膜增生。移植物受体的脾脏中保留有限稀释分析可检测到的供体反应性细胞毒性T淋巴细胞和辅助性T淋巴细胞，并产生高滴度的供体反应性同种异体抗体。在一些但不是所有长期存活的移植物受体中可检测到不同数量的同种异体微嵌合体。总的来说，这些观察结果表明：（1）当使用抗CD4单克隆抗体或抗血管细胞黏附分子-1单克隆抗体进行抗排斥治疗时，长期存活的同种异体移植物及其受体实现了相似的免疫状态，尽管这两种单克隆抗体靶向的细胞谱系和分布存在重大差异；（2）这种免疫状态的特征是持续、长期的炎症和免疫过程，与急性同种异体移植排斥反应中观察到的过程非常相似；（3）尽管有这些过程，同种异体移植物仍继续发挥功能，尽管它们总是发展出一种慢性排斥样组织病理学状况，最终可能限制移植物功能。在这方面，长期存活的同种异体移植物的受体似乎对其移植物同种异体抗原不耐受。
