1997 Fiscal Year Final Research Report Summary
Treatment of Cardiac Diseases by Suppression of Cell Adhession
| Project/Area Number |
07457166
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Shinshu University |
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Principal Investigator |
ISOBE Mitsuaki Shinshu Univ., 1st Dept.of Int.M,Associate Professor, 医学部第1内科, 助教授 (80176263)
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| Co-Investigator(Kenkyū-buntansha) |
SEKIGUCHI Morie Shinshu Univ., 1st Dept.of Int.M,Professor, 医学部第1内科, 教授 (70075232)
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| Project Period (FY) |
1995 – 1997
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| Keywords | cell adhesion / selectin / peptide / monoclonal antibody / rejection / myocardial infarction / heart transplantation / immunostaining |
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| Research Abstract |
The purposes of the present study were to evaluate roles of cell adhesion molecules in the various types of cardiac diseases and to test the effectiveness of blockade of cell adhesion in treating and preventing disease disorders.
The roles of these molecules in cardiac allograft rejection were studied in models of mouse, rat and monkey heterotopic heart transplantation. We found that ICAM-1, LFA-1, VCAM-1, VLA-4, P-selectin, E-selectin are important in eliciting cardiac rejection. Importance of differential development of Th1 and Th2 cytokines in the induction of antigen-specific tolerance by anti-ICAM-1 and anti-LFA-1 monoclonal antibodies was demonstrated. Also, significant role of E-selectin and P-selectin was revealed as evidenced by the fact that administration of monoclonal antibodies to these molecules was effective in prolongation of cardiac allograft survival.
Induction of ICAM-1 and VCAM-1 in vascular endothelium of chronically rejected cardiac allograft was found in our models of murine and monkey heart transplantation. This intimal hyperplasia could not be suppressed by conventional immunosuppressants but could be suppressed by immunological tolerance induction by short-term administration of anti-ICAM-1 and anti-LFA-1 monoclonals. We are currently evaluating roles of E- and P-selectin in the pathophysiology of rat model of balloon injury, effects of monoclonal antibodies to these adhesion molecules on the development of the intimal thickening are also currently investigated.
We have developed a couple of low molecular weight peptides which are comprised of amino acid sequence in the lectin domain of the P-selectin molecule. We showed that these peptides are effective in reduction of myocardial infarct size if they were administered at the time of coronary reperfusion in a rat model. However, because of extreme insolubility to water these peptide are not appropriate for clinical application at present.
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[Publications] Suzuki J,Isobe M,Aikawa M,Kawauchi M,Shiojima I,Kobayashi N,Tojo A,Suzuki T,Kimura K,Nishikawa T,Sakai T,Sekiguchi M,Yazaki Y,Nagai R: "Nonmuscle and smooth muscle myosin heavy chain expression in rejected cardiac allografts -A study in rat and monkey models." Circulation. 94. 1118-1124 (1996)
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[Publications] Suzuki J,Isobe M,morishita R,Aoki M,Horie S,Okubo Y,Kaneda Y,Sawa Y,Matsuda H,Ogihara T,Sekiguchi M: "Prevention of Graft Arteriopathy by Antisense cdk2 kinase oligonucleotide." Nature Medicine. 3. 900-903 (1997)
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[Publications] Suzuki J,Isobe M,Aoki M,Yamazaki S,Kaneda Y,Sawa Y,Matsuda H,Ogihara T,Horie S,Okubo Y,Sekiguchi M: "Antisense Cdk2 kinase oligonucleotide inhibits ICAM-1 expression in murine cardiac allograft arteriopathy." Transplant Proc.(in press).
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[Publications] Isobe M,Suzuki J,Morishita R,Amano J,Kaneda Y,Sawa Y,Matsuda H,Ogihara T,Horie S,Okubo Y,Sekiguchi M: "Down-regulation of endothelin-1 expression in allograft coronayr arteries after gene therapy targeting cdk2kinase." Transplant Proc.(in press).
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