High levels of IL-6 and IL-8 early after pig-to-nonhuman primate kidney xenotransplantation from α1,3-galactosyltransferase gene-knockout (GTKO) pigs.

BACKGROUND

Systemic inflammation in xenograft recipients (SIXR) has been suggested to contribute to gene-edited pig xenograft failure after transplantation into nonhuman primates. Inflammation is associated with high levels of proinflammatory cytokines. We investigated selected proinflammatory cytokines (IL-6, IL-8, IL-1b, IL-12, and tumor necrosis factor [TNF]) after pig-to-baboon kidney xenotransplantation.

METHODS

Cytokines were measured during the first 60 days after the transplantation of kidneys from either (i) α1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 3) or (ii) triple-knockout pigs with additional knockout of growth hormone receptors and transgenic expression of 6 human 'protective' proteins (10GE pigs) (n = 4): All recipients received an immunosuppressive regimen based on anti-CD154mAb, IL-6R blockade (with tocilizumab), rapamycin, and methylprednisolone.

RESULTS

Baboons with GTKO pig kidneys required euthanasia on days 47, 61, and 69 (mean 59 days) for a variety of unexplained complications (loss of mobility, loss of weight, recurrent severe ascites), but all with functioning grafts and no anti-donor pig antibodies. All recipients of 10GE pig kidneys survived for >3 months. Serum creatinine in both groups remained within the near-normal range for >3 months. IL-6 and IL-8 levels increased significantly in the GTKO group but not in the 10GE group. There was no increase in any other cytokine in either group.

CONCLUSIONS

There was a greater response of IL-6 and IL-8 to a GTKO kidney than to a 10GE kidney. Although our data are limited, it appears that multiple genetic modifications (e.g., triple knockout and/or human protective transgenes) might be necessary to overcome high levels of IL-6 and IL-8 in the early phase after xenotransplantation.