Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?
Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?
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DOI：
10.1111/ajt.15712
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发表时间：
2020-01-03
影响因子：
8.8
通讯作者：
Hara, Hidetaka
中科院分区：
文献类型：
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作者：
Zhang, Guoqiang;Iwase, Hayato;Hara, Hidetaka
白细胞介素(IL)-6/IL-6受体- α (IL- 6r α)/信号转导和转录激活3 （STAT3）通路在炎症中起重要作用。托珠单抗（TCZ）阻断抗人IL-6R α已用于猪-狒狒器官异种移植模型，但是否有益仍不确定。异种移植后，狒狒血清中IL-6和猪IL-6均显著升高，特别是在异种移植前接受TCZ治疗的狒狒。体外观察表明，人、狒狒和猪的IL-6分别可以激活人、狒狒和猪细胞中的IL-6/IL-6R α /STAT3通路。在人和狒狒细胞中，TCZ阻断了IL-6/IL-6R α /STAT3通路的激活，但在猪细胞（即猪IL-6R）中没有阻断。西妥昔单抗（人IL-6抑制剂）与人和狒狒结合，但不与猪结合，IL-6和抑制IL-6/IL-6R α /STAT3通路的激活。这些结果表明，TCZ和西妥昔单抗分别与猪IL-6R和猪IL-6没有交叉反应。雷帕霉素部分抑制人、狒狒和猪IL-6/IL-6R α /STAT3通路，抑制炎症基因表达。TCZ治疗增加了血清IL-6，因为它不再与狒狒IL-6R α结合。我们认为血清IL-6升高可能对猪异种移植物有害，因为它可能与猪IL-6R结合，导致猪细胞活化。
The interleukin (IL)-6/IL-6 receptor-alpha (IL-6R alpha)/signal transduction and activation of the transcription 3 (STAT3) pathway plays an important role in inflammation. Anti-human IL-6R alpha blockade by tocilizumab (TCZ) has been used in pig-to-baboon organ xenotransplant models, but whether it is beneficial remains uncertain. After xenotransplant, there were significant increases in both baboon and pig IL-6 in the baboon serum, especially in baboons that received TCZ before xenotransplant. In vitro observations demonstrated that human, baboon, and pig IL-6 can activate the IL-6/IL-6R alpha/STAT3 pathway in human, baboon, and pig cells, respectively. Activation of the IL-6/IL-6R alpha/STAT3 pathway was blocked by TCZ in human and baboon cells but not in pig cells (ie, pig IL-6R). Siltuximab (human IL-6 inhibitor) bound to both human and baboon, but not pig, IL-6 and suppressed activation of the IL-6/IL-6R alpha/STAT3 pathway. These results indicate that TCZ and siltuximab do not cross-react with pig IL-6R and pig IL-6, respectively. Rapamycin partially inhibited human, baboon, and pig IL-6/IL-6R alpha/STAT3 pathways and suppressed inflammatory gene expression. TCZ treatment increased serum IL-6 because it could no longer bind to baboon IL-6R alpha. We suggest that increased serum IL-6 may be detrimental to the pig xenograft because it is likely to bind to pig IL-6R, resulting in activation of pig cells.