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Physiol. Genomics (September 9, 2003). doi:10.1152/physiolgenomics.00086.2003 Free Article
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Submitted on May 19, 2003
Accepted on August 27, 2003

Identificaton of gene expression profile in tolerizing murine cardiac allograft by co-stimulatory blockade

Yuichi Matsui1, Akio Saiura1, Yasuhiko Sugawara2, Masataka Sata3, Katsutoshi Naruse2, Hideo Yagita4, Takahide Kohro5, Chikage Mataki5, Akashi Izumi5, Takuhiro Yamaguchi6, Takashi Minami5, Toshiko Sakihama5, Sigeo Ihara7, Hiroyuki Aburatani7, Takao Hamakubo5, Tatsuhiko Kodama5*, and Masatoshi Makuuchi2

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

* To whom correspondence should be addressed. E-mail: kodama{at}lsbm.org.

The induction of specific tolerance would be the ultimate achievement in transplant immunology, but the precise mechanisms of immunological 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 CD86 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 proinflammatory 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 post transplant. These results provide evidence that immunological tolerance can be induced and maintained in the presence of prominent proinflammatory gene expression in vivo.




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