Treatment of Cardiac Diseases by Suppression of Cell Adhession

本研究的目的是评估细胞粘附分子在各种心脏疾病中的作用，并测试阻断细胞粘附在治疗和预防疾病中的有效性。在小鼠、大鼠和猴异体心脏移植模型中研究了这些分子在异体心脏移植排斥反应中的作用。我们发现ICAM-1、LFA-1、VCAM-1、vca -4、p -选择素、e -选择素在诱发心脏排斥反应中起重要作用。证明了Th1和Th2细胞因子的差异发育在抗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，e -选择素和p -选择素的重要作用也被证实，针对这些分子的单克隆抗体在延长同种异体心脏移植存活方面是有效的。我们在小鼠和猴心脏移植模型中发现慢性排斥心脏移植血管内皮诱导ICAM-1和VCAM-1。这种内膜增生不能被常规免疫抑制剂抑制，但可以通过短期给药抗icam -1和抗lfa -1单克隆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中的病理生理作用，目前也在研究这些粘附分子的单克隆抗体对内膜增厚发展的影响。我们已经开发了一对低分子量肽，它们是由p -选择素分子凝集素结构域的氨基酸序列组成的。我们发现，如果在大鼠模型冠状动脉再灌注时给药，这些肽在减少心肌梗死面积方面是有效的。然而，由于这些肽对水极不溶性，目前还不适合临床应用。

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.