Schroder Paul M, Schmitz Robin, Fitch Zachary W, Ezekian Brian, Yoon Janghoon, Choi Ashley Y, Manook Miriam, Barbas Andrew, Leopardi Frank, Song Mingqing, Farris Alton B, Collins Bradley, Kwun Jean, Knechtle Stuart J
Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
Department of Pathology, Emory School of Medicine, Atlanta, Georgia, USA.
Kidney Int. 2021 Jan;99(1):161-172. doi: 10.1016/j.kint.2020.08.020. Epub 2020 Sep 6.
Sensitized patients are difficult to transplant due to pre-formed anti-donor immunity. We have previously reported successful desensitization using carfilzomib and belatacept in a non-human primate (NHP) model. Here we evaluated selective blockade of the co-stimulatory signal (CD28-B7) with Lulizumab, which preserves the co-inhibitory signal (CTLA4-B7). Five maximally MHC-mismatched pairs of NHPs were sensitized to each other with two sequential skin transplants. Individuals from each pair were randomized to either desensitization with once-weekly Carfilzomib (27mg/m IV) and Lulizumab (12.5mg/kg SC) over four weeks, or no desensitization (Control). NHPs then underwent life-sustaining kidney transplantation from their previous skin donor. Rhesus-specific anti-thymocyte globulin was used as induction therapy and immunosuppression maintained with tacrolimus, mycophenolate, and methylprednisolone. Desensitized subjects demonstrated a significant reduction in donor-specific antibody, follicular helper T cells (CD4PD-1ICOS), and proliferating B cells (CD20Ki67) in the lymph nodes. Interestingly, regulatory T cell (CD4CD25CD127) frequency was maintained after desensitization in addition to increased frequency of naïve CD4 T cells (CCR7CD45RA) and naïve B cells (IgDCD27CD20) in circulation. This was associated with significant prolongation in graft survival (MST = 5.8 ± 4.0 vs. 64.8 ± 36.3; p<0.05) and lower antibody-mediated rejection scores compared to control animals. However, all desensitized animals eventually developed AMR and graft failure. Desensitization with CFZ and Lulizumab improves allograft survival in allosensitized NHPs, by transient control of the germinal center and shifting of the immune system to a more naive phenotype. This regimen may translate into clinical practice to improve outcomes of highly sensitized transplant patients.
由于预先形成的抗供体免疫，致敏患者难以进行移植。我们之前曾报道在非人类灵长类动物（NHP）模型中使用卡非佐米和贝拉西普成功实现脱敏。在此，我们评估了用鲁利珠单抗选择性阻断共刺激信号（CD28 - B7），该方法可保留共抑制信号（CTLA4 - B7）。五对最大程度MHC不匹配的NHP通过两次连续的皮肤移植相互致敏。每对中的个体被随机分为两组，一组在四周内每周一次接受卡非佐米（27mg/m²静脉注射）和鲁利珠单抗（12.5mg/kg皮下注射）进行脱敏，另一组不进行脱敏（对照组）。然后，NHP接受来自其先前皮肤供体的维持生命的肾脏移植。使用恒河猴特异性抗胸腺细胞球蛋白作为诱导治疗，并使用他克莫司、霉酚酸酯和甲泼尼龙维持免疫抑制。脱敏的受试者在淋巴结中显示出供体特异性抗体、滤泡辅助性T细胞（CD4⁺PD - 1⁺ICOS⁺）和增殖性B细胞（CD20⁺Ki67⁺）显著减少。有趣的是，除了循环中幼稚CD4⁺T细胞（CCR7⁺CD45RA⁺）和幼稚B细胞（IgD⁺CD27⁻CD20⁺）频率增加外，脱敏后调节性T细胞（CD4⁺CD25⁺CD127⁻）频率得以维持。这与移植物存活时间显著延长（中位存活时间 = 5.8 ± 4.0天 vs. 64.8 ± 36.3天；p<0.05）以及与对照动物相比抗体介导的排斥反应评分降低相关。然而，所有脱敏动物最终都发生了急性抗体介导的排斥反应（AMR）和移植物失败。用CFZ和Lulizumab进行脱敏可通过短暂控制生发中心并将免疫系统转变为更幼稚的表型，改善同种致敏NHP的同种异体移植物存活。这种方案可能转化为临床实践，以改善高度致敏移植患者的治疗结果。
