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Novel Insights into Blocking the IL-6 / IL-6 Receptor Pathway after Pig Kidney Xenotransplantation in Baboons

H. Hara1, G. Zhang1, H. Iwase1, T. Yamamoto1, D. Ayares2, D. E. Eckhoff1, D. K. Cooper1

1Surgery, University of Alabama at Birmingham, Birmingham, AL, 2Revivicor Inc., Blacksburg, VA

Meeting: 2019 American Transplant Congress

Abstract number: D71

Keywords: Inflammation, Kidney transplantation, Primates

Session Information

Session Name: Poster Session D: Xenotransplantation

Session Type: Poster Session

Date: Tuesday, June 4, 2019

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Hall C & D

*Purpose: IL-6 plays an important role in inflammation. The aims of the study were (i) to measure IL-6 in serum in baboons that received IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) after pig kidney xenotransplantation (xenoTx), and (ii) to explore strategies to block the human/pig IL-6 – human/pig IL-6R signal pathways of phosphorylation of STAT3 (pSTAT3).

*Methods: Both baboon and pig IL-6 were measured in baboon sera after kidney xenoTx (n=14). pSTAT3 in PBMCs and aortic endothelial cells (AECs) from human and pig was measured by flow cytometry after stimulation with human or pig IL-6 with/without TCZ, IL-6 inhibition (with siltuximab: STX), or mTOR inhibition (with rapamycin) in vitro.

*Results: There were significant increases in both baboon and pig IL-6 in baboon sera after Tx (at euthanasia, baboon: p<0.05, pig: p<0.01). Both human and pig IL-6 activated pSTAT3 signaling in human and pig cells. In both human PBMCs and AECs, TCZ inhibited human/pig IL-6 - human IL6R signal pathways in a dose-dependent manner. (Maximum inhibition was 100% at a TCZ concentration of 312.5µg/mL, p<0.01). TCZ did not block the human/pig IL-6 – pig IL-6R signal pathways (in either pig PBMCs or AECs). STX inhibited human IL-6 – human/pig IL6R signal pathways in a dose-dependent manner. (Maximum inhibition was 100% at a STX concentration of 12.5µg/mL, p<0.01). STX did not block the pig IL-6 – human/pig IL-6R signal pathways. Rapamycin significantly suppressed the human/pig IL-6 – human/pig IL-6R signal pathways in dose-dependent manners. (Maximum inhibition was 50% at a rapamycin concentration of 40ng/mL, p<0.01).

*Conclusions: A transient/continuous increase of IL-6 in a recipient who received TCZ might be detrimental to a pig xenograft because there is no cross-reactivity of TCZ with the pig IL-6R. After pig-to-primate organ xenoTx, the administration of a combination of TCZ, STX, and rapamycin might suppress all human/pig IL-6 – human/pig IL-6R signal pathways. Development of a monoclonal antibody that cross-reacts with pig IL-6R or of a pig IL-6 inhibitor might be beneficial. Alternatively, genetic engineering of the pig could be carried out to knockout pig IL-6R and replace it with human IL-6R, thus protecting the organ from the injurious effects of IL-6-mediated inflammation.

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To cite this abstract in AMA style:

Hara H, Zhang G, Iwase H, Yamamoto T, Ayares D, Eckhoff DE, Cooper DK. Novel Insights into Blocking the IL-6 / IL-6 Receptor Pathway after Pig Kidney Xenotransplantation in Baboons [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/novel-insights-into-blocking-the-il-6-il-6-receptor-pathway-after-pig-kidney-xenotransplantation-in-baboons/. Accessed June 7, 2025.

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