Matsumura Y, Zuo X J, Prehn J, Linsley P S, Marchevsky A, Kass R M, Matloff J M, Jordan S C
Department of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, California 90048.
Transplantation. 1995 Feb 27;59(4):551-8.
The efficacy of CTLA4Ig in blocking immune activation and allograft rejection (AR) was tested in an aggressive and rapid model of rat lung AR (Brown Norway [BN]-->Lewis [LEW]). CTLA4Ig is a recombinant soluble protein that binds with high affinity to rat B7/BB1 and other surface molecules on APCs, subsequently blocking the binding of B7/BB1 to CD28/CTLA4 on T cells. This interrupts the costimulatory pathway critical for complete T cell activation and completion of the AR process. Left single-lung transplants were performed between BN-->Lew. Five allograft recipients were examined in each group. At transplantation, animals received 250 micrograms of CTLA4Ig or 250 micrograms of control Ig intraperitoneally daily until sacrifice. Animals were sacrificed on days 2, 4, and 7 after transplant. Control (BN-->Lew) grafts show irreversible rejection by day 7. Syngeneic (Lew-->Lew) grafts show no AR on day 7. AR episodes were graded histologically (stages 0-IV) and pathologic intensity of inflammation was graded on percentage of involvement. Cytokine transcript levels were measured in control and CTLA4Ig-treated animals (n = 5 in each group) on day 7 using reverse transcriptase polymerase chain reaction techniques. The most profound differences were found on day 7 after transplant. The degree of lymphocytic infiltration was greater in the CTLA4Ig group (perivascular: 4 +/- 0 vs. 2.6 +/- 0.6, peribronchial: 4 +/- 0 vs. 2.2 +/- 0.4, and peribronchiolar: 3.6 +/- 0.5 vs. 2 +/- 0.3, P < 0.01). However, in striking contrast, the stage of AR (3 +/- 0 vs. 4 +/- 0, P < 0.01), vasculitis (1 +/- 0.7 vs. 2.6 +/- 0.6, P < 0.05), hemorrhage (0.4 +/- 0.6 vs. 3.2 +/- 0.4, P < 0.01), and necrosis (0 +/- 0 vs. 2.4 +/- 0.5, P < 0.005) were significantly reduced in animals treated with CTLA4Ig. Since CTLA4Ig blocks Th1 cell activation in vitro, we compared the levels of Th1 inflammatory cytokines IL-2, gamma-IFN, and TNF-alpha in the two models. The intragraft ratios (CTLA4Ig/control) were IL-2:0.77, gamma-IFN: 1.29, and TNF-alpha:1.33. Thus, CTLA4Ig did not significantly block intragraft production of Th1 cytokines on day 7.(ABSTRACT TRUNCATED AT 400 WORDS)
在大鼠肺急性排斥反应（AR）的一种侵袭性快速模型（棕色挪威大鼠[BN]→刘易斯大鼠[LEW]）中测试了CTLA4Ig在阻断免疫激活和同种异体移植排斥反应方面的疗效。CTLA4Ig是一种重组可溶性蛋白，它与大鼠B7/BB1及抗原呈递细胞（APC）上的其他表面分子具有高亲和力结合，随后阻断B7/BB1与T细胞上CD28/CTLA4的结合。这中断了对完全T细胞激活和AR过程完成至关重要的共刺激途径。在BN→LEW之间进行左单肺移植。每组检查5只同种异体移植受体。在移植时，动物每天腹腔内注射250微克CTLA4Ig或250微克对照Ig，直至处死。在移植后第2、4和7天处死动物。对照（BN→LEW）移植物在第7天显示出不可逆的排斥反应。同基因（LEW→LEW）移植物在第7天未显示AR。AR发作通过组织学分级（0 - IV期），炎症的病理强度根据受累百分比分级。在移植后第7天，使用逆转录聚合酶链反应技术测量对照和CTLA4Ig处理动物（每组n = 5）中的细胞因子转录水平。在移植后第7天发现了最显著的差异。CTLA4Ig组的淋巴细胞浸润程度更高（血管周围：4±0对2.6±0.6，支气管周围：4±0对2.2±0.4，细支气管周围：3.6±0.5对2±0.3，P < 0.01）。然而，与之形成鲜明对比的是, CTLA4Ig处理的动物中AR的阶段（3±0对4±0，P < 0.01）、血管炎（1±0.7对2.6±0.6，P < 0.05）、出血（0.4±0.6对3.2±0.4，P < 0.01）和坏死（0±0对2.4±0.5，P < 0.005）均显著降低。由于CTLA4Ig在体外阻断Th1细胞激活，我们比较了两种模型中Th1炎性细胞因子IL - 2、γ - 干扰素和肿瘤坏死因子 - α的水平。移植物内比率（CTLA4Ig/对照）分别为IL - 2：0.77、γ - 干扰素：1.29和肿瘤坏死因子 - α：1.33。因此，在第7天CTLA4Ig并未显著阻断移植物内Th1细胞因子的产生。（摘要截短为400字）
