Treatment of Cardiac Diseases by Suppression of Cell Adhession

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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.