Antibody-Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology.
Antibody-Mediated Rejection in Sensitized Nonhuman Primates: Modeling Human Biology.
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DOI：
10.1111/ajt.13688
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发表时间：
2016-06
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影响因子：
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通讯作者：
Knechtle SJ
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文献类型：
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作者：
Burghuber CK;Kwun J;Page EJ;Manook M;Gibby AC;Leopardi FV;Song M;Farris AB 3rd;Hong JJ;Villinger F;Adams AB;Iwakoshi NN;Knechtle SJ
我们已经在非人类灵长类动物中建立了致敏模型，并测试了两种免疫抑制方案。进行完全错配皮肤移植的动物，通过血流交叉匹配监测供体特异性抗体（DSA）反应。致敏动物随后接受皮肤供体的肾移植。免疫抑制包括他克莫司、麦考酚酸酯和甲基强的松龙。3只动物接受basiliximab诱导，与未致敏的动物相比，它们的平均生存时间更短（MST, 4.7±3.1 vs 187±88天）。6只小鼠经t细胞清除（抗cd4 /CD8单抗）治疗后，存活时间延长（MST=21.6±19.0天）。所有预致敏动物均出现抗体介导的排斥反应（AMR）。2/3 basiliximab动物细胞排斥反应（ACR）明显。T细胞耗损后，3/6的猴子在8天内出现早期急性排斥反应，并伴有血栓性微血管病变和AMR的组织学证据。其余3例存活27 ~ 44天，AMR和ACR混合。大多数t细胞耗尽的动物经历了与肾功能恶化相关的DSA反弹。我们还发现增殖记忆B细胞（CD20+CD27+IgD−Ki67+），淋巴结滤泡辅助T细胞（ICOS+PD-1hiCXCR5+CD4+）和生发中心反应增加。在致敏的非人灵长类动物中，耗竭控制细胞介导的排斥反应优于巴西昔单抗，但移植物排斥反应伴随着DSA升高。该模型为测试新的脱敏策略提供了机会。
We have established a model of sensitization in non-human primates and tested two immunosuppressive regimens. Animals underwent fully mismatched skin transplantation, donor-specific antibody (DSA) response was monitored by flow crossmatch. Sensitized animals subsequently underwent kidney transplantation from their skin donor. Immunosuppression included tacrolimus, mycophenolate and methylprednisolone. Three animals received basiliximab induction, compared to non-sensitized animals they showed a shorter mean survival time (MST, 4.7±3.1 vs. 187±88 days). Six animals were treated with T-cell depletion (anti-CD4/CD8 mAbs), which prolonged survival (MST=21.6±19.0 days). All pre-sensitized animals showed antibody-mediated rejection (AMR). In 2/3 basiliximab animals cellular rejection (ACR) was prominent. After T cell depletion, 3/6 monkeys experienced early acute rejection within 8 days with histological evidence of thrombotic microangiopathy and AMR. The remaining three survived 27 to 44 days, with mixed AMR and ACR. Most T-cell depleted animals experienced a rebound of DSA that correlated with deteriorating kidney function. We also found an increase in proliferating memory B cells (CD20+CD27+IgD−Ki67+), lymph node follicular helper T cells (ICOS+PD-1hiCXCR5+CD4+) and germinal center response. Depletion controlled cell-mediated rejection in sensitized non-human primates better than basiliximab, yet grafts were rejected with concomitant DSA rise. This model provides an opportunity to test novel desensitization strategies.