Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL.
Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL.
Transplantation. 2021 Jun 1;105(6):1143-1155. doi: 10.1097/TP.0000000000003622.
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
我们讨论了在首次临床试验中使用基因工程猪肾或心脏移植时，哪种治疗方案可能是可接受/成功的。由于基于钙调神经磷酸酶抑制剂或 CTLA4-Ig 的方案已被证明不成功，因此我们在狒狒中使用的方案是基于抗胸腺细胞球蛋白、抗 CD20 mAb（利妥昔单抗）和眼镜蛇毒液因子的诱导治疗，维持治疗基于阻断 CD40/CD154 共刺激途径（使用抗 CD40 mAb），联合雷帕霉素和皮质类固醇。在前 2 周内使用抗炎药（依那西普），辅助治疗包括预防血栓并发症、贫血、巨细胞病毒和肺囊虫病。使用这种方案，虽然确实会发生抗体介导的排斥反应，但我们没有发现针对猪异种移植物的适应性免疫反应的明确证据。该方案也可以作为首次临床试验的基础，但眼镜蛇毒液因子将被一种临床批准的药物替代，例如 C1-酯酶抑制剂。然而，目前还没有任何一种阻断 CD40/CD154 途径的药物被批准用于临床，因此这一障碍仍需克服。抗炎药物的作用仍未得到证实。与同种异体移植中使用的方案相比，该建议方案的主要区别在于用共刺激阻断剂替代钙调神经磷酸酶抑制剂，但这似乎并未增加方案的并发症。
