3 Deazaadenosin prevents leukocyte evasion by suppression of adhesion molecule expression during acute cardiac allograft rejection

Abstract

In the initial phase after cardiac transplantation, mononuclear cells infiltrate the graft initiating a relevant impulse for rejection. 3-Deazaadenosin (c3Ado), an analogue of adenosine, has demonstrated in vitro anti-inflammatory properties. Furthermore in vivo studies on arteriosclerosis development and septic myocardial dysfunction c3Ado revealed reduced cellular infiltration. In addition ischemia and reperfusion injury could be diminished in a pulmonary animal model. Therefore, the aim of our study was to investigate the properties of c3Ado to reduce adhesion molecule expression and cellular infiltration in a fully allogeneic cardiac transplant model. LEW rats were challenged with WF cardiac allografts. Untreated grafts were rejected within 7 days (group1). In group 2, animals received 2x5mg c3Ado s.c./day. Grafts were harvested on day 1,3, and 6 after transplantation for further examination (n=4, per group and time point). Immunohistochemical examination revealed significant reduction of graft infiltrating MHC II positive cells, T-cell receptor positive cells (R73) as well as ED1 positive monocytes and macrophages (p < 0.002-0.0001) at day 1-6 after transplantation. Adhesion molecule (ICAM-1,VCAM-1) expression on day 1 and 3 after transplantation was almost completely diminished in c3Ado treated grafts. Therefore, c3Ado is able to reduce graft infiltration by preventing leukocyte evasion through the suppression of adhesion molecule expression. This might be a novel strategy to protect transplanted organs from early damage after transplantation and extend organ survival after transplantation.