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 present investigation was to evaluate the macrophage response and its relationship to the programmed death of cardiomyocytes in rejection and during cyclosporin-A (CsA) treatment. An abdominal, heterotopic heart transplant rat model was used establishing two groups: singenic (ST) and allogenic (AL) transplant. 5 mg/kg/day (s.c.) CsA (Sandimun) was administered to half of the animals in each group. Morphological and structural analysis was performed 7, 14, 21, 30, 50 and 100 days post-transplant. Macrophages were detected using the monoclonal antibody (ED1). The TUNEL method was used to visualise apoptotic cells. Two weeks after ST in animals without immuno-suppressive treatment, the transplanted myocardium had been extensively infiltrated by inflammatory cells, many of which were ED1-positive. At 21 days follow-up, the number of labelled cells had fallen. In animals treated with CsA the amount of ED1-positive 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 took place between 9-15 days in the untreated animals. The myocardium was highly 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 response 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 treatment diminishes the amount of infiltrated macrophages; b) animals receiving ST or AT, show a low level of apoptosis; c) in the present model, the apoptosis of cardiomyocytes does not appear to be induced by macrophages; and d) in this model it is not possible to relate apoptosis and rejection.
Jurado
F
F
Department of Morphological Sciences and Surgery (Surgical Research Laboratory), Faculty of Medicine, University of Alcalá de Henares, Madrid, Spain.
Bellón
J M
JM
Golitsin
A
A
Gimeno
M J
MJ
Pascual
G
G
Buján
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine