Yuh D D, Gandy K L, Morris R E, Hoyt G, Gutierrez J, Reitz B A, Robbins R C
Department of Cardiothoracic Surgery, Stanford University Medical Center, Calif, USA.
J Heart Lung Transplant. 1995 Nov-Dec;14(6 Pt 1):1136-44.
Leflunomide, an isoxazole derivative, has been shown to effectively prolong rodent allograft and cardiac xenograft survival. In vitro studies suggest that leflunomide inhibits the production of donor-specific antibodies and is capable of blocking both T- and B-cell proliferation. In light of the significant role that humoral immunity is believed to play in chronic pulmonary allograft rejection as well as hyperacute and accelerated acute xenograft rejection, we examined the efficacy of leflunomide in prolonging pulmonary allografts and xenografts and its effect on donor-specific antibody production.
Lungs from Brown Norway rats or Golden Syrian hamsters were orthotopically transplanted into Lewis rat recipients. Allograft recipients were treated daily for 14 days with vehicle, leflunomide (15 mg/kg/day orally), or cyclosporine (7.5 mg/kg/day orally) starting on the day of grafting (day 0). In xenograft recipients, leflunomide (20 mg/kg/day orally) or cyclosporine (7.5 mg/kg/day orally) treatment initiated on day 0 was continued until complete graft rejection; the leflunomide dosage was reduced to 10 mg/kg/day after day 14 because of weight loss and leukopenia. Graft viability was assessed with chest radiography in conjunction with open lung biopsies. Toxicity was monitored with body weight measurements, complete blood counts, and serum chemistries. Flow cytometric analysis of serum samples taken from graft recipients on day 7 was used to measure donor-specific immunoglobulin M and immunoglobulin G antibody titers.
Allograft and xenograft control animals receiving vehicle yielded graft survival times of 6.0 +/- 0.0 and 5.4 +/- 0.6 days, respectively. Although xenograft recipients treated with cyclosporine (7.5 mg/kg/day orally) showed no significant graft prolongation, pulmonary allograft survival in recipients receiving cyclosporine alone was significantly prolonged to 28.2 +/- 0.7 days. Leflunomide-treated allograft (15 mg/kg/day orally) and xenograft (20 mg/kg/day orally) recipients displayed significant graft prolongation to 28.2 +/- 0.7 days and 15.8 +/- 3.3 days, respectively. Cyclosporine (7.5 mg/kg/day orally) enhanced the effect of leflunomide (20 mg/kg/day orally) in xenograft recipients with a mean graft survival time of 36.0 +/- 3.0 days achieved when both drugs were administered concomitantly. Cyclosporine significantly suppressed donor-specific immunoglobulin G antibody titers in both pulmonary allograft and xenograft recipients while not affecting immunoglobulin M levels. Leflunomide markedly suppressed both immunoglobulin G and immunoglobulin M donor-specific antibody titers in allograft and xenograft recipients. Except for mild leukopenia and anemia, both cyclosporine- and leflunomide-treated allograft recipients showed no evidence of toxic side effects after 14 days of therapy. However, leflunomide-treated xenograft recipients displayed significant weight loss, anemia, and leukopenia after 14 days of treatment with one death in each treatment group.
来氟米特是一种异恶唑衍生物，已被证明能有效延长啮齿动物同种异体移植和心脏异种移植的存活时间。体外研究表明，来氟米特可抑制供体特异性抗体的产生，并能阻断T细胞和B细胞的增殖。鉴于体液免疫被认为在慢性肺同种异体移植排斥反应以及超急性和加速急性异种移植排斥反应中起重要作用，我们研究了来氟米特在延长肺同种异体移植和异种移植存活时间方面的疗效及其对供体特异性抗体产生的影响。
将棕色挪威大鼠或金黄叙利亚仓鼠的肺原位移植到Lewis大鼠受体中。同种异体移植受体在移植当天（第0天）开始每天接受14天的载体、来氟米特（15mg/kg/天口服）或环孢素（7.5mg/kg/天口服）治疗。在异种移植受体中，从第0天开始的来氟米特（20mg/kg/天口服）或环孢素（7.5mg/kg/天口服）治疗持续到移植完全排斥；由于体重减轻和白细胞减少，第14天后将来氟米特剂量减至10mg/kg/天。通过胸部X线摄影结合开放性肺活检评估移植存活情况。通过体重测量、全血细胞计数和血清化学检测监测毒性。对移植受体在第7天采集的血清样本进行流式细胞术分析，以测量供体特异性免疫球蛋白M和免疫球蛋白G抗体滴度。
接受载体的同种异体移植和异种移植对照动物的移植存活时间分别为6.0±0.0天和5.4±0.6天。虽然口服环孢素（7.5mg/kg/天）治疗的异种移植受体的移植存活时间没有显著延长，但单独接受环孢素治疗的同种异体移植受体的肺移植存活时间显著延长至28.2±0.7天。接受来氟米特治疗的同种异体移植（15mg/kg/天口服）和异种移植（20mg/kg/天口服）受体的移植存活时间分别显著延长至28.2±0.7天和15.8±3.3天。环孢素（7.5mg/kg/天口服）增强了来氟米特（20mg/kg/天口服）对异种移植受体的作用，两种药物同时给药时，平均移植存活时间达到36.0±3.0天。环孢素显著抑制同种异体移植和异种移植受体中供体特异性免疫球蛋白G抗体滴度，而不影响免疫球蛋白M水平。来氟米特显著抑制同种异体移植和异种移植受体中免疫球蛋白G和免疫球蛋白M供体特异性抗体滴度。除轻度白细胞减少和贫血外，接受环孢素和来氟米特治疗的同种异体移植受体在治疗14天后均未显示出毒性副作用的证据。然而，来氟米特治疗的异种移植受体在治疗14天后出现显著体重减轻、贫血和白细胞减少，每个治疗组有1只死亡。
