Shimizu A, Yamada K, Sachs D H, Colvin R B
Department of Pathology, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Kidney Int. 2000 Dec;58(6):2546-58. doi: 10.1046/j.1523-1755.2000.00440.x.
Inbred miniature swine treated for 12 days with high-dose cyclosporine A develop tolerance to histocompatibility complex (MHC) class I-mismatched renal allografts. When this protocol was modified by adding thymectomy before transplant, all animals developed acute rejection. Thereafter, by day 100, one half developed chronic rejection (progression group) and the other half recovered (recovery group). This provides an excellent experimental model to identify the mechanisms of chronic rejection as well as the early changes that may predict chronic rejection.
We assessed the cellular infiltration, immune activation, humoral immunity, and cell- and antibody-mediated graft injury in the progression and the recovery groups. In addition, we also examined circulating donor reactive cytotoxic T lymphocyte (CTL) and antidonor antibody in both groups.
From days 8 to 18 after transplantation, the two groups were indistinguishable. Both showed acute rejection with endarteritis (type II); had IgG and IgM deposition in glomeruli and small vessels; had an infiltrate with similar numbers of T cells, proliferating (PCNA+) and activated (interleukin-2 receptor+) cells; and had a similar degree of parenchymal cell apoptosis [in situ DNA nick-end labeling (TUNEL)+]. However, by days 30 to 60, the two groups could be distinguished by several intragraft features. The recovery group became tolerant and had diminished T-cell infiltration, activation and proliferation, and no detectable antibody deposition. The number of TUNEL+-injured parenchymal cells decreased. In contrast, the progression group showed persistent cell infiltration with activation and proliferation. Significantly prominent TUNEL+ apoptotic parenchymal cells in tubules, glomeruli, peritubular capillaries and arteries were seen from day 30 to day 100. Circulating donor reactive CTL and antidonor class I IgG were detected in the progression group at higher levels than in the recovery group from days 30 to 60.
In tolerance-induction protocols, unstable tolerance induction is associated with the persistent immunologic activation that mediates immunologic destruction of graft parenchymal cells and chronic rejection. Certain of the described immunopathologic findings (activation, proliferation, apoptosis, and antibody deposition) may be useful in distinguishing the type of rejection, that is, whether the allograft will progress to chronic rejection or recovery.
用高剂量环孢素A治疗12天的近交系小型猪对组织相容性复合体（MHC）I类不匹配的肾移植产生耐受性。当通过在移植前增加胸腺切除术来修改该方案时，所有动物均发生急性排斥反应。此后，到第100天时，一半动物发生慢性排斥反应（进展组），另一半动物恢复（恢复组）。这为确定慢性排斥反应的机制以及可能预测慢性排斥反应的早期变化提供了一个极好的实验模型。
我们评估了进展组和恢复组中的细胞浸润、免疫激活、体液免疫以及细胞和抗体介导的移植物损伤。此外，我们还检测了两组中循环的供体反应性细胞毒性T淋巴细胞（CTL）和抗供体抗体。
移植后第8天至18天，两组无明显差异。两组均表现为伴有动脉内膜炎的急性排斥反应（II型）；肾小球和小血管中有IgG和IgM沉积；浸润的T细胞数量相似，增殖（增殖细胞核抗原阳性，PCNA+）和活化（白细胞介素-2受体阳性）细胞数量相似；实质细胞凋亡程度相似[原位DNA缺口末端标记法（TUNEL）阳性]。然而，到第30天至60天时，两组可通过移植物内的几个特征加以区分。恢复组产生耐受性，T细胞浸润、活化和增殖减少，未检测到抗体沉积。TUNEL阳性的损伤实质细胞数量减少。相比之下，进展组表现为持续的细胞浸润并伴有活化和增殖。从第30天到第100天，在肾小管、肾小球、肾小管周围毛细血管和动脉中可见到明显突出的TUNEL阳性凋亡实质细胞。在第30天至60天期间，进展组中循环的供体反应性CTL和抗供体I类IgG的检测水平高于恢复组。
在耐受性诱导方案中，不稳定的耐受性诱导与持续的免疫激活有关，这种免疫激活介导移植物实质细胞的免疫破坏和慢性排斥反应。某些所述的免疫病理学发现（活化、增殖、凋亡和抗体沉积）可能有助于区分排斥反应的类型，即同种异体移植物是否会进展为慢性排斥反应或恢复。
