Abstract
BackgroundIn pig-to-baboon transplantation models, there is increasing evidence of systemic inflammation in xenograft recipients (SIXR) associated with pig xenograft failure. We evaluated the relationship between systemic inflammatory factors and pig kidney xenograft failure.MethodsBaboons received kidney transplants from genetically engineered pigs (n=9), and received an anti-CD40mAb-based (n=4) or conventional (n=5) immunosuppressive regimen. The pig kidney grafts were monitored by measurements of serum creatinine, serum amyloid A (SAA), white blood cell (WBC) and platelet counts, plasma fibrinogen, and pro-inflammatory cytokines (baboon and pig IL-6, TNF-α, IL-1β).ResultsSix baboons were euthanized or died from rejection, and 3 were euthanized for infection. Changes in serum creatinine correlated with those of SAA (r=0.56, p<0.01). Serum baboon IL-6 was increased significantly on day 1 after transplantation and at euthanasia (both p<0.05) and correlated with serum creatinine and SAA (r=0.59, p<0.001, r=0.58, p<0.01; respectively). but no difference was observed between rejection and infection. Levels of serum pig IL-6, TNF-α, IL-1β were also significantly increased on day 1 and at euthanasia, and serum pig IL-6 and IL-1β correlated with serum creatinine and SAA. The level of serum baboon IL-6 correlated with the expression of IL-6 and amyloid A in the baboon liver (r=0.93, p<0.01, r=0.79, p<0.05; respectively).ConclusionEarly upregulation of SAA and serum IL-6 may indicate the development of rejection or infection, and are associated with impaired kidney graft function. Detection and prevention of systemic inflammation may be required to prevent pig kidney xenograft failure after xenotransplantation.
Highlights
Organ transplantation is the preferred method of treatment of end-stage organ failure, but a severe shortage of deceased human donor organs is a major limitation
We suggest that systemic inflammatory response in the xenograft recipient (SIXR) may be closely associated with pig kidney graft failure, and the detection and prevention of an inflammatory response may play an important role in prolonging the survival of a pig xenograft in a nonhuman primate (NHP)
Serum creatinine rose in the days before euthanasia became necessary (Figure 1B), but there was no significant difference between the Rejection and Infection groups on day 1 or at euthanasia (Figure 1C), in the Infection group the serum creatinine was significantly increased in only one baboon (B9313) at euthanasia
Summary
Organ transplantation is the preferred method of treatment of end-stage organ failure, but a severe shortage of deceased human donor organs is a major limitation. The pig has since been identified as a potential source of organs for clinical transplantation [1], but there remain several barriers in pig-to-primate organ xenotransplantation that have to be overcome. One of these is the systemic inflammatory response in the xenograft recipient (SIXR) to the presence of a pig organ [2,3,4]. In pig-to-baboon transplantation models, there is increasing evidence of systemic inflammation in xenograft recipients (SIXR) associated with pig xenograft failure. We evaluated the relationship between systemic inflammatory factors and pig kidney xenograft failure
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