PAF antagonists have been used in
xenotransplantation to alleviate the pathogenesis of hyperacute rejection. This study evaluated the ability of the PAF antagonist
UR-12670 to improve graft function in late xenograft rejection (LXR) in an orthotopic liver
xenotransplantation model, and the involvement of PAF (
platelet activating factor) in this type of rejection. The recipients of a hamster xenograft received standard immunosuppression (
tacrolimus 0.2 mg/kg/30 days, MMF 25 mg/kg/8 days). Study groups: group A, without
UR-12670, group B,
UR-12670 (20 mg/kg/8 d) and group C, continuous administration of
UR-12670 (20 mg/kg/d). Serum levels of
xenoantibodies were evaluated by flow cytometry and tissue deposits by immunofluorescence. Immunoblot and indirect immunofluorescence assessed specificity of
xenoantibodies. Conventional histology was performed. Continuous administration of
UR-12670 improved the histological pattern of liver xenografts, especially
necrosis, loss of hepatocytes,
hemorrhage, sinusoidal congestion and lymphocyte infiltration. There was not a shift in specificity of
xenoantibodies at different times posttransplantation, as demonstrated by immunoblotting and indirect immunofluorescence.
UR-12670 administration had a beneficial effect on graft function and considerably improved the histopathological pattern, but it failed to induce tolerance after withdrawal of immunosuppression.
UR-12670 had an immunomodulatory effect on cellular response but not on antibody production. There was not a change in the specificity of
xenoantibodies produced at LXR compared with pretransplant
antibodies.