2005 Fiscal Year Final Research Report Summary
New biomarkers for acute rejection and therapeutic effect of immunosuppressive drugs in organ transplantation
| Project/Area Number |
16590121
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Keio University |
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Principal Investigator |
MIHARA Kiyoshi Keio University, School of Medicine, Department of Pharmacy, Instructor, 医学部, 助手 (00281444)
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| Co-Investigator(Kenkyū-buntansha) |
TANABE Minoru Keio University, School of Medicine, Department of Surgery, Assistant Professor, 医学部, 講師 (50197513)
TANIGAWARA Yusuke Keio University, School of Medicine, Department of Pharmacy, Professor, 医学部, 教授 (30179832)
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| Project Period (FY) |
2004 – 2005
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| Keywords | organ transplantation / immunosuppressive drugs / biomarkers / cDNA microarray / rat / rejection / PK / PD analysis |
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| Research Abstract |
In organ transplantation, needle biopsy of allograft is a standard test for the diagnosis of acute rejection. However, sampling errors, biopsy-associated complications, and a time-consuming process are problem. The aim of this study is to search and identify new biomarkers for allograft rejection and therapeutic effect of immunosuppressive drugs by measuring gene expression profile in peripheral blood. We carried out the rat cardiac and liver transplantation to create three models, isograft, allograft, and allograft with cyclosporine (CsA). White blood cells in the peripheral bloods were collected to perform gene expression profiling using DNA microarray analysis. Ten candidate genes were selected in the DNA microarray analysis followed by quantitative PCR confirmation. The expression of all candidate genes in the peripheral blood were significantly elevated several days before graft loss due to acute rejection but showed no change in the isograft and CsA treated models. A relationship between the CsA trough concentration and the gene expression could be well described by a sigmoid Emax model. The results suggested that the expression of these candidate genes in peripheral blood were good predictors for rejection episode and therapeutic effect of CsA. Then, the gene expression in the peripheral blood was measured in pediatric patients with living-donor liver transplantation. The expression of five genes increased significantly two to six days before needle biopsy diagnosing acute rejection. A comprehensive analysis of the gene expression in peripheral blood of rat organ transplantation models results in the discovery of new biomarkers, which could be applied to the therapeutic use.
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