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.

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 November 22, 2024.

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