在灵长类心脏移植模型中，用αCD40进行延迟性ICOS/ICOS-L阻断以调节致病性同种异体免疫的初步研究。

Pilot Study of Delayed ICOS/ICOS-L Blockade With αCD40 to Modulate Pathogenic Alloimmunity in a Primate Cardiac Allograft Model.

作者信息

O'Neill Natalie A, Zhang Tianshu, Braileanu Gheorghe, Cheng Xiangfei, Hershfeld Alena, Sun Wenji, Reimann Keith A, Dahi Sia, Kubicki Natalia, Hassanein Wessam, Laird Christopher, Cimeno Arielle, Azimzadeh Agnes M, Pierson Richard N

机构信息

Department of Surgery, University of Maryland School of Medicine, Baltimore, MD.

MassBiologics, University of Massachusetts Medical School, Boston, MA.

出版信息

Transplant Direct. 2018 Feb 2;4(2):e344. doi: 10.1097/TXD.0000000000000761. eCollection 2018 Feb.

BACKGROUND

Inducible costimulator (ICOS) is rapidly upregulated with T-cell stimulation and may represent an escape pathway for T-cell costimulation in the setting of CD40/CD154 costimulation blockade. Induction treatment exhibited no efficacy in a primate renal allograft model, but rodent transplant models suggest that the addition of delayed ICOS/ICOS-L blockade may prolong allograft survival and prevent chronic rejection. Here, we ask whether ICOS-Ig treatment, timed to anticipate ICOS upregulation, prolongs NHP cardiac allograft survival or attenuates pathogenic alloimmunity.

METHODS

Cynomolgus monkey heterotopic cardiac allograft recipients were treated with αCD40 (2C10R4, d0-90) either alone or with the addition of delayed ICOS-Ig (d63-110).

RESULTS

Median allograft survival was similar between ICOS-Ig + αCD40 (120 days, 120-125 days) and αCD40 (124 days, 89-178 days) treated animals, and delayed ICOS-Ig treatment did not prevent allograft rejection in animals with complete CD40 receptor coverage. Although CD4 T cells were decreased in peripheral blood (115 ± 24) and mLNs (49 ± 1.9%) during ICOS-Ig treatment compared with monotherapy (214 ± 27%, = 0.01; 72 ± 9.9%, = 0.01, respectively), acute and chronic rejection scores and kinetics of alloAb elaboration were similar between groups.

CONCLUSIONS

Delayed ICOS-Ig treatment with the reagent tested is probably ineffective in modulating pathogenic primate alloimmunity in this model.

背景

诱导性共刺激分子（ICOS）在T细胞受到刺激时会迅速上调，在CD40/CD154共刺激阻断的情况下，它可能代表T细胞共刺激的一种逃逸途径。诱导治疗在灵长类动物肾移植模型中未显示出疗效，但啮齿动物移植模型表明，延迟给予ICOS/ICOS配体（ICOS-L）阻断剂可能会延长移植物存活时间并预防慢性排斥反应。在此，我们探讨在预计ICOS上调时给予ICOS-Ig治疗是否能延长非人灵长类动物（NHP）心脏移植物存活时间或减轻致病性同种异体免疫反应。

方法

食蟹猴异位心脏移植受者单独接受αCD40（2C10R4，第0天至第90天）治疗，或在接受αCD40治疗的基础上延迟给予ICOS-Ig（第63天至第110天）。

结果

接受ICOS-Ig + αCD40治疗的动物（120天，120 - 125天）与接受αCD40治疗的动物（124天，89 - 178天）的移植物中位存活时间相似，并且延迟给予ICOS-Ig治疗并不能预防CD40受体完全被覆盖的动物发生移植物排斥反应。尽管与单一疗法相比，在ICOS-Ig治疗期间外周血中的CD4 T细胞数量减少（115 ± 24），肠系膜淋巴结中的CD4 T细胞数量减少（49 ± 1.9%）（分别为214 ± 27%，P = 0.01；72 ± 9.9%，P = 0.01），但两组之间的急性和慢性排斥反应评分以及同种异体抗体产生的动力学相似。