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Overcoming Barriers to Survival following Pig-to-Baboon Liver Xenotransplantation
*Jigesh A Shah, *Matthew J O'Neil, James F. Markmann, *David H. Sachs, Parsia A. Vagefi
Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA
Objective: Assess rejection following pig-to-baboon liver xenotransplantation (LXT)
Design: Large animal research
Setting: Laboratory
Patients: Baboon recipients of porcine livers (n=8)
Interventions: Human prothrombin concentrate complex (Octaplex), Human Recombinant Factor 7a (Novoseven)
Main Outcome Measures: In-vitro and immunohistological detection of rejection
Results: Following LXT, baboons received continuous Novoseven (n=3) or Octaplex as a bolus (n=2) or as a continuous infusion (n=3). Immunosuppression consisted of an induction dose of thymoglobulin, maintenance therapy with continuous FK506, and a methylprednisone taper. In addition, two baboons received co-stimulation blockade (belatacept). All recipients underwent serum assessment for circulating baboon anti-pig immunoglobulins (IgM and IgG) via fluorescence-activated cell sorting (FACS) analysis. The presence of circulating IgM was detected in only one recipient on post-operative (POD) 7, with subsequent resolution by POD 14. This correlated clinically with an increase in liver function tests consistent with rejection and resolved following treatment with pulse-dose corticosteroids. On further analysis these antibodies were confirmed to be circulating cytotoxic IgM. No baboons demonstrated the presence of antibody deposition on immunohistochemistry staining of liver biopsies. Furthermore, all recipients of continuous coagulation factor administration demonstrated normal hepatic architecture, minimal inflammation, no evidence of cellular rejection, and an absence of thrombotic microangiopathy.
Conclusions: Our findings suggest that the immunological hurdles to xenotransplantation are surmountable as conventional immunosuppressive protocols are capable of maintaining liver xenograft survival up to 25 days without the development of rejection. Graft failure appears to be an end result of coagulopathy, thrombocytopenia and cholestasis attributed to interspecies incompatibilities. Further work in overcoming these barriers is underway in an effort to potentially allow pig-to-baboon LXT to serve as a bridge to allotransplantation in patients with acute hepatic failure.
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