Cytokine profiles in Tibetan macaques following α‐1,3‐galactosyltransferase‐knockout pig liver xenotransplantation

Abstract

Here, we established a modified auxiliary liver xenotransplantation model resulting in near-normal hepatic function. Inflammatory cytokines might contribute to early damage in liver xenografts. Controlling the systemic inflammatory response of recipients might prevent early post-Tx graft dysfunction.

Potential pathological role of pro‐inflammatory cytokines (IL‐6, TNF‐α, and IL‐17) in xenotransplantation

“…IL‐6 is upregulated in both donor xenograft and recipients in xenotransplantation . IL‐6 was induced in adult porcine islets treated with poly I:C or LPS in vitro, administration of LPS also induced IL‐6 expression in pig‐to‐mouse islet xenotransplantation .…”

“…Interestingly, in a pig‐to‐baboon model, induced IL‐6 was not significantly less after the transplantation of cardiac grafts from pigs with multiple genetic modifications (eg, GTKO, hCD46, hEPCR, hDAF in addition to either hTFPI and hCD47 [n = 2] or hTBM and hCD39 [n = 1]) when compared to pigs with only three genetic manipulations (GTKO, hCD46, and hTBM) (Table ) . Moreover, Zhang et al reported that the production of IL‐6 increased dramatically 1 hour after pig‐to‐monkey liver xenotransplantation with immunosuppressive therapy, but the level of IL‐6 gradually fell from day 1 to day 10 (Table ). However, the transplantation of porcine islets transduced with human HO‐1, sTNF‐αR‐Fc (soluble TNF‐α receptor type I with human IgG1 Fc), or sTNF‐αR‐Fc/HO‐1 was associated with a decrease in the level of IL‐6 compared to a control group (Table ) …”

A review of pig liver xenotransplantation: Current problems and recent progress

“…Leukocyte, erythrocyte, and platelet sequestration can occur either during ex vivo perfusion or after in vivo transplantation, associated with adhesion and capture mechanisms, and these could be exacerbated by increased cytokine production, cell desialylation, and interspecies incompatibilities . Kupffer cells in the pig liver and circulating macrophages release proinflammatory and procoagulant factors that augment graft injury .…”

“…8,9 In particular, profound platelet loss results in lethal hemorrhage. 10,11 We here provide a systematic review of the present status of pig liver xenotransplantation and summarize relevant molecular mechanisms related to xenogeneic immunity, coagulation dysregulation, and thrombocytopenia. Our purpose is to consider strategies to overcome the current barriers to further advance pig liver transplantation toward the clinic.…”

“…Nevertheless, pig liver xenograft survival is limited to less than a month (Figure ) due to major unresolved problems, particularly relating to coagulation dysregulation . In particular, profound platelet loss results in lethal hemorrhage …”