Presensitized Immune Condition of Host Exaggerates Prolonged Cold Ischemia-Mediated Injury of Cardiac Graft Involving Regulatory T Cells
Presensitized Immune Condition of Host Exaggerates Prolonged Cold Ischemia-Mediated Injury of Cardiac Graft Involving Regulatory T Cells
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DOI：
10.1097/tp.0b013e31829df26d
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
W. Gong;Tao Huang;F. Ge;Gaojian Luo;Shunzong Yuan;Daming Gao;D. Kong
中科院分区：
文献类型：
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作者：
W. Gong;Tao Huang;F. Ge;Gaojian Luo;Shunzong Yuan;Daming Gao;D. Kong
背景长时间冷缺血（PCI）对移植移植物预致敏的不利影响是可以想象的，但受体预致敏状态对PCI介导的移植物损伤和炎症的影响尚不明确。方法将BALB/c供体同种异体皮肤移植到C57BL/6受体体内进行致敏。同种异体或同种异体异位心脏移植与PCI通过不同的治疗方法使用C57BL/6或BALB/c供体。结果PCI不能影响同种异体移植物的存活，但能显著缩短同种异体移植物的存活时间。用抗cd25单克隆抗体在心脏移植前后1天开始消耗调节性T细胞（Tregs），可显著诱导移植体内Foxp3基因表达，加重结构损伤和心外膜下及肌肉内炎性细胞浸润，导致移植体内CD4+/CD8+比值急剧下降。而通过雷帕霉素促进外源性野生型Tregs或内源性Tregs过继转移，对防止T淋巴细胞和Gr-1+中性粒细胞的浸润，逆转移植体内CD4+/CD8+比值，保存心脏移植物结构具有有益作用。然而，它们独特的保护机制表明，雷帕霉素治疗主要是减少CD4+ t细胞浸润。然而，在移植物中，CD4+细胞的数量仍然超过CD8+ T细胞，而Tregs的过继性转移使CD4+和CD8+ T细胞，特别是CD8+ T细胞扩增。结论同种异体免疫应答可协同增强缺血条件下PCI的疗效。PCI可能影响随后的免疫反应。treg密切参与了这一病理生理过程。我们的数据可能为使用Tregs作为一种新的治疗方法来预防pci介导的移植受者损伤铺平道路。
Background The detrimental effect of prolonged cold ischemia time (PCI) on presensitized transplanted graft is conceivable, but the impact of presensitization status of recipient on PCI-mediated graft injury and inflammation is not well defined. Methods Allogeneic skin grafts from BALB/c donors were transplanted into C57BL/6 recipients for presensitization. Syngeneic or allogeneic heterotopic heart transplantations with PCI were performed using C57BL/6 or BALB/c donors for these recipients through different treatments. Results We revealed that PCI could not affect isograft survival but significantly shortened allograft survival in the presensitized recipients. Depletion of regulatory T cells (Tregs) starting 1 day before and after heart transplantation with anti-CD25 monoclonal antibody remarkably induced intragraft Foxp3 gene expression, worsened architecture damage and subepicardial and intramuscle inflammatory cellular infiltration, and caused a dramatic fall of intragraft CD4+/CD8+ ratio, whereas adoptive transfer of exogenous wild-type Tregs or endogenous Tregs promoted by rapamycin had a beneficial effect on preventing the infiltration of T lymphocytes and Gr-1+ neutrophils and reversed intragraft CD4+/CD8+ ratio, preserving cardiac graft architecture. However, their distinct protective mechanisms showed that rapamycin treatment mainly diminished CD4+ T-cell infiltration. Nevertheless, CD4+ still outnumbered CD8+ T cells in the graft, whereas adoptive transfer of Tregs expanded both CD4+ and CD8+ T cells, particularly CD8+ T cells. Conclusion Allogeneic immunoresponses synergistically enhanced PCI effect under presensitized condition. PCI could affect subsequent immunoresponses. Tregs were closely involved in this pathophysiologic process. Our data may pave the way to use Tregs as a novel therapeutic approach to prevent PCI-mediated injury in the presensitized transplant recipients.