Role of macrophages in myocardial apoptosis following cardiac transplant. Influence of immunosuppressive treatment

Cytotoxic T cells may induce myocardial apoptosis by histiocyte activation during rejection following allogenic heart transplant. The aim of the prese nt investigation was to evaluate the macrophage response and its relationsh ip to the programmed death of cardiomyocytes in rejection and during cyclos porin-A (CsA) treatment. An abdominal, heterotopic heart transplant rat model was used establishing two groups: singenic (ST) and allogenic (AL) transplant. 5mg/kg/day (s.c.) CsA (Sandimun(R)) was administered to half of the animals in each group. Mo rphological and structural analysis was performed 7, 14, 21, 30, 50 and 100 days post-transplant. Macrophages were detected using the monoclonal antib ody (ED1). The TUNEL method was used to visualise apoptotic cells. Two weeks after ST in animals without immunosuppressive treatment, the tran splanted myocardium had been extensively infiltrated by inflammatory cells, many of which were ED1-positive. At 21 days follow-up, the number of label led cells had fallen. In animals treated with CsA the amount of ED1-positiv e cells was lower than that seen in the anterior group. Only a few isolated cells of the infiltrate were TUNEL-positive. In the AT group, rejection to ok place between 9-15 days in the untreated animals. The myocardium was hig hly infiltrated by mononuclear cells. Some were ED1-positive. Small groups of apoptotic cells were visible in the infiltrate and in some vessel lumens . Rejection was resolved in animals treated with CsA. The macrophage respon se diminished during follow-up in a similar way to that occurring in the ST . Few cells showed TUNEL positivity. It may be concluded that: a) CsA treat ment diminishes the amount of infiltrated macrophages; b) animals receiving ST or AT, show a low level of apoptosis; c) in the present model, the apop tosis of cardiomyocytes does not appear to be induced by macrophages; and d ) in this model it is not possible to relate apoptosis and rejection.