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Physiol. Genomics 15: 199-208, 2003. First published September 9, 2003; doi:10.1152/physiolgenomics.00086.2003 Free Article
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Received 19 May 2003; accepted in final form 27 August 2003.
Physiological Genomics 15:199-208 (2003)
1094-8341/03 $5.00 © 2003 American Physiological Society

Identification of gene expression profile in tolerizing murine cardiac allograft by costimulatory blockade

Yuichi Matsui1,6, Akio Saiura1,6, Yasuhiko Sugawara1, Masataka Sata2, Katsutoshi Naruse1, Hideo Yagita3, Takahide Kohro6, Chikage Mataki6, Akashi Izumi6, Takuhiro Yamaguchi4, Takashi Minami6, Toshiko Sakihama6, Sigeo Ihara5, Hiroyuki Aburatani5, Takao Hamakubo6, Tatsuhiko Kodama6 and Masatoshi Makuuchi1

1 Departments of Hepato-Biliary-Pancreatic and Transplantation Surgery
2 Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
3 Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421
4 Biostatistics/ Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, Tokyo 113-8655
5 Genome Sciences, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan
6 Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan

The induction of specific tolerance would be the ultimate achievement in transplant immunology, but the precise mechanisms of immunologic tolerance remain largely unknown. Here, we investigated global gene expression analysis in tolerizing murine cardiac allografts by means of oligonucleotide microarrays. Tolerance induction was achieved in cardiac allografts from BALB/c to C57BL/6 mice by daily intraperitoneal injection of anti-CD80 and anti-CD86 monoclonal antibodies (mAbs). Comparative analysis revealed 64 genes to be induced more extensively in the tolerizing than in the syngeneic isografts, and 16 genes than in the rejecting allografts. Two genes were specifically upregulated in the tolerizing allografts. In the tolerizing allografts there were induced marked expressions of a number of genes for pro-inflammatory factors, including interferon-{gamma}-inducible cytokines and chemokines, as well as apoptosis-related genes, which were also upregulated in the rejecting allografts. Moreover, these gene expression patterns continued to be upregulated more than 70 days posttransplant. These results provide evidence that immunologic tolerance can be induced and maintained in the presence of prominent pro-inflammatory gene expression in vivo.

transplantation; immunologic tolerance; interferon-{gamma}; chemokine; DNA microarray




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