| Project/Area Number |
10670636
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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 |
Circulatory organs internal medicine
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| Research Institution | NIIGATA UNIVERSITY |
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Principal Investigator |
KODAMA Makoto School of Medicine, NIIGATA UNIVERSITY, Lecturer, 医学部, 講師 (10242447)
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| Co-Investigator(Kenkyū-buntansha) |
FURUKAWA Tatsuo University Medical Hospital, NIIGATA UNIVERSITY, Associate Professor, 医学部・附属病院, 助教授 (00272849)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | myocarditis / experimental autoimmune myocarditis / CD2 / coxsakievirus adenovius receptor / natriuretic peptides / cytokine / Fas / Fas ligand / 予後規定因子 / sFas / sFasL / IL-10 / 心サルコイド-シス / CAR / carvedilol / 心筋炎 / T細胞受容体 / アポトーシス |
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| Research Abstract |
Cardiac myosin-induced rat experimental autoimmune myocarditis (EAM) is an animal model of human giant cell myocarditis. After the acute fulminant phase, EAM leads to post-myocarditis dilated cardiomyopathy. Pathogenesis of autoimmune myocardial injuries was investigated using EAM.Initially, we analyzed structure of the T-cell receptor complementarity determining region 3 (CDR3) of T-cells infiltrating in myocardium. When rats were immunized with cardiac myosin rod protein, CDR3 motif of the heart infiltrating T-cells were restricted. Cardiac myosin rod protein contains several myocarditogenic epitopes. When EAM was induced by immunization with a synthetic myocarditogenic peptide, heart infiltrating T-cells were oligoclonal. Analysis of CDR4 motif of t-cells in the lesion may be a marker for autoimmune pathogenesis (Circulation Research 83 : 133-140, 1998). Cytokines play important roles in the pathogenesis of autoimmune myocardial injuries. IL-12 promotes Th0 T-cells into T-cells with
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Th1 function. Messenger RNA of IL-12 was expressed in the myocardium in EAM.Effects of IL-12 were investigated. In vivo administration of IL-12 shifted the natural course of EMA to severe and persistent form. Thus, Th1 polarity related to the onset, progression and persistence of EAM (Circulation Research 82 : 1035-1042, 1998). Coxsakievirus and adenovirus receptor (CAR) has recently been found and its gene has been cloned. This molecule may be related to susceptibility of myocarditis. We investigated expression of CAR in the rat hearts with EAM.CAR was expressed on the neonatal myocardium, but it could not be detected on the adult rat heart. During the course of EAM, mRNA of CAR was expressed on the myocardium from 18 days after immunization. Immunohistochemistry also revealed expression of CAR on the myocardium from day 24. In vitro studies demonstrated that myocardial expression of CAR was induced by inflammatory cytokines (Circulation Research 86 : 275-280, 2000).
Clinical manifestation of myocarditis vary from asymptomatic to fulminant and fatal form. The predictors of the course of the disease in patients with myocarditis have not yet been established. We examined the predictive values of various parameters in the disease course of patients with acute myocarditis. We collected human cases of myocarditis in Niigata prefecture. Twenty-one consecutive patients with histology-proven myocarditis were analyzed. Thirteen patients could survive acute phase and remainder were died. The fatal group had lower blood pressure and higher pulmonary capillary wedge pressure compared with the survival group. Serum levels of soluble Fas and Fas ligand were significantly higher in the fatal group than the survival group. Soluble Fas and Fas ligand would be serological marker to predict prognosis in patients with myocarditis (Circulation 102 : 2829-2835, 2000). Less
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