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.
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.
Bartlett
Adam S
AS
Division of Surgery, University of Auckland, New Zealand.
McCall
John L
JL
Ameratunga
Rohan
R
Howden
Brian
B
Yeong
Mee-Ling
ML
Benjamin
Christopher D
CD
Hess
Donna
D
Peach
Robert
R
Munn
Stephen R
SR
D000069594:Abatacept; D000818:Animals; D000906:Antibodies / Q000009:adverse effects / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000517:prevention & control*; D018796:Immunoconjugates; D007136:Immunoglobulins / Q000009:adverse effects / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D016031:Liver Transplantation; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects
D000906:Antibodies; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D012333:RNA, Messenger; D023201:CD40 Ligand; D000069594:Abatacept; D016572:Cyclosporine; D001219:Aspartate Aminotransferases