Blockade of inducible costimulator pathway to prevent acute rejection in rat liver transplantation

• Published in: The American journal of surgery 2009-08, Vol.198 (2), p.244-249
• Main Authors: Chen, Yong, Ph.D, Liu, Haizhong, M.D, Liu, Zuojin, Ph.D, Liang, Shaoyong, Ph.D, Chen, Jie, M.D, Long, Feiwu, M.D, Peng, Yong, Ph.D, Yan, Lünan, Ph.D, Gong, Jianping, Ph.D
• Format: Article
• Language: English
• Subjects: Acute rejection; Allografts; Animals; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - immunology; Apoptosis; Biological and medical sciences; Blotting, Western; CD25 antigen; Down-Regulation; Gene expression; General aspects; Graft rejection; Graft Rejection - prevention & control; Grafts; Immunity; Immunohistochemistry; Immunological tolerance; In Situ Nick-End Labeling; Indicators and Reagents; Inducible costimulator; Inducible T-Cell Co-Stimulator Protein; Infiltration; Interference; Interferon; Interferon-gamma - blood; Lipids; Live transplantation; Liver; Liver - metabolism; Liver - pathology; Liver transplantation; Liver Transplantation - immunology; Liver transplants; Liver, biliary tract, pancreas, portal circulation, spleen; Lymphocytes; Lymphocytes T; Medical sciences; Metastases; Microscopy; mRNA; Plasma levels; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Rats; Rejection; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA interference; RNA, Messenger - metabolism; RNA-mediated interference; Rodents; siRNA; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the digestive system; Survival; T cell receptors; T lymphocyte; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Transfection; Transplantation; Tumor Necrosis Factor-alpha - blood; Tumor necrosis factor-α; γ-Interferon
• ISSN: 0002-9610; 1879-1883
• DOI: 10.1016/j.amjsurg.2008.09.014

Abstract Background The role of inducible costimulator (ICOS) in transplantation immunity remains unclear. Methods A Lewis-to-Brown–Norway (BN) rat liver transplant model was used to explore the effect of ICOS blockade by small interference RNA. Recipient survival rate, number of CD25/ICOS–positive cells, ICOS mRNA and protein levels, and interferon-γ and tumor-necrosis factor-α levels were determined. Results Recipient survival was significantly prolonged in rats treated with RNA interference. On day 7 after transplantation, there was a diminished frequency of CD25/ICOS–positive cells and an increased frequency of apoptotic T cells. Furthermore, we found that ICOS blockade could inhibit mRNA and protein expression of ICOS, decrease plasma levels of interferon-γ and tumor-necrosis factor-α, suppress cell infiltration into grafts, and promote tolerance in the interference group. Conclusions Our data demonstrate that RNA interference is a potent tool to down-modulate ICOS expression and protect allografts from acute rejection.