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Is interleukin‐6 receptor blockade (tocilizumab) beneficial or detrimental to pig‐to‐baboon organ xenotransplantation?
Author(s) -
Zhang Guoqiang,
Iwase Hayato,
Wang Liaoran,
Yamamoto Takayuki,
Jagdale Abhijit,
Ayares David,
Li Yong,
Cooper David K. C.,
Hara Hidetaka
Publication year - 2020
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15712
Subject(s) - baboon , tocilizumab , xenotransplantation , medicine , interleukin , interleukin 6 , inflammation , biology , immunology , pharmacology , endocrinology , cytokine , transplantation , rheumatoid arthritis
The interleukin (IL)‐6/IL‐6 receptor‐α (IL‐6Rα)/signal transduction and activation of the transcription 3 (STAT3) pathway plays an important role in inflammation. Anti‐human IL‐6Rα 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‐6Rα/STAT3 pathway in human, baboon, and pig cells, respectively. Activation of the IL‐6/IL‐6Rα/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‐6Rα/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‐6Rα/STAT3 pathways and suppressed inflammatory gene expression. TCZ treatment increased serum IL‐6 because it could no longer bind to baboon IL‐6Rα. 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.