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Treatment of Cardiac Diseases by Suppression of Cell Adhession

通过抑制细胞粘附治疗心脏病

基本信息

批准号：
07457166
负责人：
ISOBE Mitsuaki
金额：
$ 4.67万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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.

为探讨细胞粘附分子在各种心脏疾病中的作用，以及阻断细胞粘附在治疗和预防疾病中的作用，本研究采用小鼠、大鼠和猴异位心脏移植模型，研究了细胞粘附分子在心脏移植排斥反应中的作用。ICAM-1、LFA-1、VCAM-1、VLA-4、P-选择素、E-选择素在心脏排斥反应中起重要作用。证明了Th 1和Th 2细胞因子的差异发展在抗ICAM-1和抗LFA-1单克隆抗体诱导抗原特异性耐受中的重要性。此外，显着的作用，E-选择素和P-选择素被揭示的事实证明，这些分子的单克隆抗体的管理是有效的延长心脏移植物survival.Induction的ICAM-1和VCAM-1在血管内皮细胞的慢性排斥的心脏移植被发现在我们的小鼠和猴心脏移植模型。这种内膜增生不能被传统的免疫抑制剂抑制，但可以通过短期给予抗ICAM-1和抗LFA-1单克隆抗体诱导免疫耐受来抑制。我们目前正在评估E-和P-选择素在大鼠球囊损伤模型的病理生理学中的作用，这些粘附分子的单克隆抗体对内膜增厚的发展的影响也正在研究中，我们已经开发了一对低分子量肽，其由P-选择素分子的凝集素结构域的氨基酸序列组成。我们表明，如果在大鼠模型中冠状动脉再灌注时给予这些肽，则它们在减少心肌梗死面积方面是有效的。然而，由于这些肽极不溶于水，目前不适合临床应用。