Background: Xenotransplantation of genetically modified pig heart has been discussed as an alternative to alleviate a shortage of donor hearts in clinical transplantation. Although life-supporting function of genetically modified pig hearts in nonhuman-primates over 6 months have been reported, cardiac xenografts are commonly rejected within a month in nonhuman primates and the rejection mechanism are not well understood. Here, we investigated chronological changes in cytokine profiles in NHP recipients after porcine cardiac xenotransplantation to understand changes in biological and immunological responses in the recipients.
Methods: Porcine hearts from α-galactosyltransferase knockout pigs were transplanted into two cynomolgus monkeys, that received anti-CD154 based immune suppression. EDTA plasma was collected from them at following time points: 1 week before transplantation (TPx), immediate before TPx (0 h), 2 h, 3 d, and 7 d after TPx and weekly thereafter until the graft failed. The levels of following cytokines in the plasma were measured by flow cytometry or ELISA: Interleukin (IL)-1A, IL-1B, IL-6, IL-12p70, IL-8, IL-10, IL-15, tumor necrotizing factor (TNF) and interferon-gamma (IFNg).
Results: The levels of IL-6 and IL-15 in both cases and of IL-1A and IL-1B in one case increased rapidly at 2 h after TPx, decreased to basal levels at 3 d of TPx and escalated again with deterioration of recipients’ general condition. On the other hand, the levels of IL-8, IL-10, IL-12p70 and TNF did not change significantly. Interestingly, the levels of IFNg increased at 7 d of TPx, which preceded a soar of IL-6, IL-8 and IL-15 followed by the graft failure.
Conclusions: Cytokine changes suggest that the acute vascular responses which appear immediately after TPx could be limited by an appropriate treatment but gradual appearance of IFNg response at later time points, indicating activation of immune cells, would be associated with subsequent graft rejection.