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Costimulatory blockade prevents early rejection, promotes lymphocyte apoptosis, and inhibits the upregulation of intragraft interleukin‐6 in an orthotopic liver transplant model in the rat
Author(s) -
Bartlett Adam S.,
McCall John L.,
Ameratunga Rohan,
Howden Brian,
Yeong MeeLing,
Benjamin Christopher D.,
Hess Donna,
Peach Robert,
Munn Stephen R.
Publication year - 2002
Publication title -
liver transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.814
H-Index - 150
eISSN - 1527-6473
pISSN - 1527-6465
DOI - 10.1053/jlts.2002.32979
Subject(s) - medicine , cd8 , isotype , liver transplantation , terminal deoxynucleotidyl transferase , immunology , mixed lymphocyte reaction , transplantation , blockade , cd154 , immunosuppression , lymphocyte , immune system , t cell , cd40 , cytotoxic t cell , antibody , immunohistochemistry , biology , tunel assay , monoclonal antibody , receptor , biochemistry , in vitro
Abstract Costimulatory pathways have a pivotal role in the T‐cell response to alloantigen. The role of costimulatory blockade with anti‐CD154 in orthotopic liver transplantation (OLT) has not been examined previously. This study aims to investigate effects of anti‐CD154 and CTLA4‐immunoglobulin (Ig) in the early post‐OLT period using a major histocompatibility complex–disparate fully arterialized OLT model in the rat. Lewis rats underwent OLT with Dark Agouti liver allografts. Recipients were randomized to receive (1) isotype control, (2) anti‐CD154, (3) CTLA4‐Ig, or (4) cyclosporine A (CyA). Rats were killed day 8, and specimens were obtained for histological examination, terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labeling, immunohistochemistry, and quantitative reverse‐transcriptase polymerase chain reaction. An additional five transplant recipients were treated with anti‐CD154 for 14 days postoperatively to assess long‐term allograft survival. All isotype control animals died on or before day 6 of acute rejection. Apart from four deaths caused by nonimmunologic causes, all treated recipients survived to day 8. The median survival of rats treated for 14 days with anti‐CD154 was greater than 150 days. Serum aspartate aminotransferase and bilirubin levels normalized by day 3 in the CyA group and day 5 in transplant recipients treated with costimulatory blockade. Histologically, there was no difference between isotype controls and CTLA4‐Ig–treated animals, whereas anti‐CD154–treated transplant recipients had a lower Banff score. CD4 + and CD8 + T‐cell infiltrates were prominent in transplant recipients treated with costimulatory blockade. Intragraft analysis showed an increase in lymphocyte apoptosis, Fas ligand messenger RNA expression, and reduction in interleukin‐6 gene expression in transplant recipients treated with costimulatory blockade. Costimulatory blockade did not alter intragraft gene expression of other mediators of T‐cell priming, differentiation, and effector function compared with isotype control animals. In conclusion, costimulatory blockade prevented acute rejection, enabled long‐term survival, and increased intragraft lymphocyte apoptosis in a high‐responding rat OLT model.