Itescu Silviu, Burke Elizabeth, Lietz Katherine, John Ranjit, Mancini Donna, Michler Robert, Rose Eric, Oz Mehmet, Edwards Niloo
College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Circulation. 2002 Mar 12;105(10):1214-9. doi: 10.1161/hc1002.105128.
The proportion of cardiac transplant recipients with preexisting sensitization to HLA alloantigens has been increasing. Sensitization prolongs duration to obtaining a donor and predicts poorer long-term allograft survival because of increased risk of cellular rejections. We investigated the effect of cyclophosphamide pulse therapy in sensitized cardiac allograft recipients.
Pretransplant and posttransplant outcomes were compared between 88 cardiac allograft recipients at risk for sensitization and 26 sensitized recipients treated with intravenous cyclophosphamide pulse therapy together with intravenous immune globulin before transplant and as part of a cyclosporine-based triple immunosuppressive regimen after transplant. Preformed IgG anti-HLA antibodies predicted longer duration to transplantation, earlier cellular rejection, and 2.7-fold higher cumulative rejection frequency (P=0.002). Before transplant, cyclophosphamide reduced waiting time and mortality to levels in nonsensitized patients. After transplant, cyclophosphamide prevented induction of IgG anti-HLA class II antibodies and interleukin-2 receptor--positive T-cell outgrowth from biopsy sites (both P<0.01), prolonged the rejection-free interval (P=0.009), and reduced cumulative rejections to levels in nonsensitized patients (P=0.003). By multivariable analysis, the risk of rejection was 3.7-fold higher in patients treated with mycophenolate mofetil than patients treated with cyclophosphamide (P=0.019). There were no differences in infectious or other significant complications.
Immunosuppression incorporating intravenous cyclophosphamide before and after transplantation is safe and highly effective in sensitized cardiac transplant recipients. When used after transplantation as part of triple immunosuppression, cyclophosphamide is superior to mycophenolate mofetil in reducing rejection. The mechanism may involve prevention of diversification of the recipient immune response to donor HLA class II molecules.
对人类白细胞抗原（HLA）同种异体抗原预先致敏的心脏移植受者比例一直在增加。致敏会延长获得供体的时间，并因细胞排斥风险增加而预示长期同种异体移植物存活较差。我们研究了环磷酰胺脉冲疗法对致敏心脏同种异体移植受者的影响。
比较了88名有致敏风险的心脏同种异体移植受者与26名在移植前接受静脉环磷酰胺脉冲疗法联合静脉注射免疫球蛋白治疗，并在移植后作为基于环孢素的三联免疫抑制方案一部分的致敏受者的移植前和移植后结果。预先形成的IgG抗HLA抗体预示移植时间更长、更早发生细胞排斥，且累积排斥频率高2.7倍（P = 0.002）。移植前，环磷酰胺将等待时间和死亡率降低到未致敏患者的水平。移植后，环磷酰胺可防止诱导IgG抗HLA II类抗体和活检部位白细胞介素-2受体阳性T细胞生长（均P<0.01），延长无排斥间隔时间（P = 0.009），并将累积排斥反应降低到未致敏患者的水平（P = 0.003）。通过多变量分析，接受霉酚酸酯治疗的患者排斥风险比接受环磷酰胺治疗的患者高3.7倍（P = 0.019）。感染或其他重大并发症方面无差异。
移植前后采用静脉注射环磷酰胺的免疫抑制方案对致敏心脏移植受者安全且高效。移植后作为三联免疫抑制的一部分使用时，环磷酰胺在减少排斥方面优于霉酚酸酯。其机制可能涉及防止受者对供体HLA II类分子的免疫反应多样化。
