Schwalb Allison M, Anwar Imran, DeLaura Isabel, Ladowski Joseph M, Yoon Janghoon, Belloni Rafaela, Song Mingqing, Glass Carolyn, Wang Jun, Knechtle Stuart, Kwun Jean
Duke Transplant Center, Duke University School of Medicine, Durham, NC, United States.
Department of Pathology, Duke University School of Medicine, Durham, NC, United States.
Front Transplant. 2024 Dec 16;3:1494455. doi: 10.3389/frtra.2024.1494455. eCollection 2024.
Cardiac Allograft Vasculopathy (CAV), a process of vascular damage accelerated by antibody-mediated rejection (AMR), is one of the leading causes of cardiac transplant failure. Proteasome inhibitors (PIs) are utilized to treat AMR, however PI-associated toxicity limits their therapeutic utility. Novel immunoproteasome inhibitors (IPIs) have higher specificity for immune cells and have not been investigated for AMR in cardiac transplant patients. We sought to evaluate IPI effect on AMR in a murine cardiac transplant model.
Fully MHC mismatched C57BL/6 to huCD52Tg heterotopic heart transplantations were performed. Recipients were treated with alemtuzumab (10 µg, IP) on days -2, -1, 2, and 4 and anti-CD25mAb (PC61, 100 µg, IP) on day 7 to accelerate AMR with or without IPI (ONX-0914,15 mg/kg, SQ), administered on transplant day and three times a week thereafter.
Animals without IPI gradually developed post-transplant donor-specific antibody (DSA) and showed a significantly elevated DSA level compared to animals receiving IPI. (TFXM 48.86 vs. 14.17; = 0.0291, BFXM 43.53 vs. 6.114; = 0.0031). Accordingly, H&E staining of allograft showed reduced evidence of AMR with IPI compared to controls ( = 0.0410). Notably, increased mortality was observed in the IPI treated group.
This study demonstrated the ability of ONYX-0914, an IPI, to control post-transplant DSA production and the AMR development in a heart transplant model. However, IPI-resistant DSA production was also observed and increased mortality with IPI therapy raises concerns about potential toxicity. Further investigation is warranted to assess the utility and potential risk associated with the use of IPI as a post-transplant maintenance immunosuppression.
心脏移植血管病变（CAV）是一种由抗体介导的排斥反应（AMR）加速的血管损伤过程，是心脏移植失败的主要原因之一。蛋白酶体抑制剂（PIs）用于治疗AMR，然而PI相关的毒性限制了它们的治疗效用。新型免疫蛋白酶体抑制剂（IPIs）对免疫细胞具有更高的特异性，尚未在心脏移植患者中针对AMR进行研究。我们试图在小鼠心脏移植模型中评估IPI对AMR的影响。
进行完全MHC不匹配的C57BL/6到huCD52Tg异位心脏移植。受体在第-2、-1、2和4天接受阿仑单抗（10μg，腹腔注射），在第7天接受抗CD25单克隆抗体（PC61，100μg，腹腔注射），以加速AMR，无论是否使用IPI（ONX-0914，15mg/kg，皮下注射），在移植日给药，此后每周三次。
未使用IPI的动物移植后逐渐产生供体特异性抗体（DSA），与接受IPI的动物相比，DSA水平显著升高。（TFXM 48.86对14.17；P = 0.0291，BFXM 43.53对6.114；P = 0.0031）。因此，与对照组相比，移植心脏的苏木精-伊红染色显示使用IPI时AMR的证据减少（P = 0.0410）。值得注意的是，在IPI治疗组中观察到死亡率增加。
本研究证明了IPI ONYX-0914在心脏移植模型中控制移植后DSA产生和AMR发展的能力。然而，也观察到了对IPI耐药的DSA产生，并且IPI治疗导致的死亡率增加引发了对潜在毒性的担忧。有必要进一步研究以评估使用IPI作为移植后维持免疫抑制的效用和潜在风险。
