Modulation of the pathology of late xenograft rejection by PAF-antagonist UR-12670 in the hamster-to-rat liver xenotransplant model.
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.
Ginesta
Mireia M
MM
Department of Surgery and Surgical Specialities, University of Barcelona School of Medicine, Catalonia.
Mollevi
David G
DG
Serrano
Teresa
T
Bas
Jordi
J
Mestre
Mariona
M
Ribas
Yolanda
Y
Figueras
Joan
J
Jaurrieta
Eduardo
E
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood; D000918:Antibody Specificity; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D006224:Cricetinae; D019084:Fluorescent Antibody Technique, Indirect; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000473:pathology / Q000502:physiology; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D008647:Mesocricetus; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D012709:Serum Albumin / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology*
D000910:Antibodies, Heterophile; D007093:Imidazoles; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D010972:Platelet Activating Factor; D011725:Pyridines; D012709:Serum Albumin; C097826:UR 12670; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase