Is interleukin-6 receptor blockade (tocilizumab) beneficial or detrimental to pig-to-baboon organ xenotransplantation?

Abstract

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.

Impact of porcine cytomegalovirus on long-term orthotopic cardiac xenotransplant survival

“…These data indicate that the up-regulation of IL-6 might promote systemic inflammation and together with the subsequent induction of C-RP leads to a dysregulation of coagulation after xenotransplantation 49 . Some studies suggest that the administration of tocilizumab, an antibody raised against the IL-6 receptor, reduced antibody-mediated rejection in post-transplantation and improved allograft survival 50 or reduced C-RP levels and other factors to alleviate consumptive coagulopathy 51 – 54 . Tocilizumab reacts with the human and baboon IL-6 receptor, but not with the pig IL-6 receptor 54 .…”

“…Some studies suggest that the administration of tocilizumab, an antibody raised against the IL-6 receptor, reduced antibody-mediated rejection in post-transplantation and improved allograft survival 50 or reduced C-RP levels and other factors to alleviate consumptive coagulopathy 51 – 54 . Tocilizumab reacts with the human and baboon IL-6 receptor, but not with the pig IL-6 receptor 54 . Blocking the baboon IL-6 receptor may lead to higher circulating levels of IL-6n in the blood and this may be detrimental to pig xenotransplant survival due to IL-6 stimulation of pig cells in the transplant.…”

Screening and identification of key regulatory connections and immune cell infiltration characteristics for lung transplant rejection using mucosal biopsies

“…Lifitegrast targets ITGB2 and is applied in the treatment of ocular chronic graft-versus-host disease [93] . Siltuximab is a human–mouse chimeric monoclonal antibody that targets human IL-6 and inhibits the IL-6 pro-inflammatory pathway in pig-to-baboon organ xenotransplantation models [94] . Belatacept is a selective co-stimulation blocker that binds to membrane CD80 and CD86 of APCs; it has been applied in immunosuppression during lung, kidney, and heart transplantation [95] , [96] , [97] .…”

Extracellular histones and xenotransplantation

“…However, more recent data indicate that tocilizumab blocks the binding of IL‐6 to primate IL‐6 receptors, but not to pig IL‐6 receptors, and thus may not be beneficial, or even detrimental, in xenotransplantation 15,16 …”