非人类灵长类心脏同种异体移植模型中αCD40（2C10R4）和αCD154（5C8H1和IDEC-131）的比较评估
Comparative Evaluation of αCD40 (2C10R4) and αCD154 (5C8H1 and IDEC-131) in a Nonhuman Primate Cardiac Allotransplant Model.
作者信息
OʼNeill Natalie A, Zhang Tianshu, Braileanu Gheorghe, Sun Wenji, Cheng Xiangfei, Hershfeld Alena, Laird Christopher T, Kronfli Anthony, Hock Lindsay A, Dahi Siamak, Kubicki Natalia, Sievert Evelyn, Hassanein Wessam, Cimeno Arielle, Pierson Richard N, Azimzadeh Agnes M
机构信息
1 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD. 2 MassBiologics, University of Massachusetts Medical School, Boston, MA.
出版信息
Transplantation. 2017 Sep;101(9):2038-2047. doi: 10.1097/TP.0000000000001836.
BACKGROUND
Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal of this study is to compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 T cell costimulation pathway.
METHODS
Cynomolgus monkey heterotopic cardiac allograft recipients were treated with either IDEC-131 (humanized αCD154, n = 9), 5C8H1 (mouse-human chimeric αCD154, n = 5), or 2C10R4 (mouse-rhesus chimeric αCD40, n = 6) monotherapy using a consistent, comparable dosing regimen for 3 months after transplant.
RESULTS
Relative to the previously reported IDEC-131-treated allografts, median survival time (35 ± 31 days) was significantly prolonged in both 5C8H1-treated (142 ± 26, P < 0.002) and 2C10R4-treated (124 ± 37, P < 0.020) allografts. IDEC-131-treated grafts had higher cardiac allograft vasculopathy severity scores during treatment relative to either 5C8H1 (P = 0.008) or 2C10R4 (P = 0.0002). Both 5C8H1 (5 of 5 animals, P = 0.02) and 2C10R4 (6/6, P = 0.007), but not IDEC-131 (2/9), completely attenuated IgM antidonor alloantibody (alloAb) production during treatment; 5C8H1 (5/5) more consistently attenuated IgG alloAb production compared to 2C10R4 (4/6) and IDEC-131 (0/9). All evaluable explanted grafts experienced antibody-mediated rejection. Only 2C10R4-treated animals exhibited a modest, transient drop in CD20 lymphocytes from baseline at day 14 after transplant (-457 ± 152 cells/μL) compared with 5C8H1-treated animals (16 ± 25, P = 0.037), and the resurgent B cells were primarily of a naive phenotype.
CONCLUSIONS
In this model, CD154/CD40 axis blockade using IDEC-131 is an inferior immunomodulatory treatment than 5C8H1 or 2C10R4, which have similar efficacy to prolong graft survival and to delay cardiac allograft vasculopathy development and antidonor alloAb production during treatment.
背景
特异性阻断T细胞共刺激通路是一种很有前景的免疫调节方法，正在研发以取代我们目前的临床免疫抑制疗法。本研究的目的是比较3种针对CD40/CD154 T细胞共刺激通路的单克隆抗体的相关结果。
方法
食蟹猴异位心脏移植受者在移植后3个月使用一致、可比的给药方案，分别接受IDEC-131（人源化αCD154，n = 9）、5C8H1（鼠-人嵌合αCD154，n = 5）或2C10R4（鼠-恒河猴嵌合αCD40，n = 6）单药治疗。
结果
相对于先前报道的接受IDEC-131治疗的同种异体移植物，接受5C8H1治疗（142±26天，P<0.002）和2C10R4治疗（124±37天，P<0.020）的同种异体移植物的中位生存时间（35±31天）均显著延长。与5C8H1（P = 0.008）或2C10R4（P = 0.0002）相比，接受IDEC-131治疗的移植物在治疗期间心脏同种异体血管病变严重程度评分更高。5C8H1（5只动物中的5只，P = 0.02）和2C10R4（6/6，P = 0.007），但不是IDEC-131（2/9），在治疗期间完全减弱了IgM抗供体同种异体抗体（alloAb）的产生；与2C10R4（4/6）和IDEC-131（0/9）相比，5C8H1（5/5）更持续地减弱了IgG alloAb的产生。所有可评估的切除移植物均经历了抗体介导的排斥反应。与接受5C8H1治疗的动物（16±25，P = 0.037）相比，仅接受2C10R4治疗的动物在移植后第14天CD20淋巴细胞相对于基线出现适度、短暂的下降（-457±152个细胞/μL），并且复苏后的B细胞主要为幼稚表型。
结论
在该模型中，使用IDEC-131阻断CD154/CD40轴的免疫调节治疗效果不如5C8H1或2C10R4，它们在延长移植物存活、延缓心脏同种异体血管病变发展以及治疗期间抗供体alloAb产生方面具有相似的疗效。
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