Histological and immunohistochemical studies using specific monoclonal antibodies were made to evaluate the severity of the chronic cardiomyopathy and the quantitative changes in interstitial dendritic cells (antigen-presenting cells), T helper lymphocytes, T cytotoxic/suppressor lymphocytes, and macrophages in the hearts of spontaneously hypertensive rats (SHRs) treated with doxorubicin at 1 mg/kg per week for 3, 6, 9 or 12 weeks. In addition, an assessment was made of the modifications of the responses of these cell populations by pretreatment of the SHR with ICRF-187, which protects against doxorubicin cardiotoxicity. The number of interstitial dendritic cells/mm2 of section of left ventricle was similar in saline-treated control SHRs (76 +/- 6) and in those treated with ICRF-187 alone (75 +/- 2) but increased markedly (319 +/- 33) in animals receiving a total cumulative dose of 12 mg/kg doxorubicin. Treatment with ICRF-187 prior to each administration of doxorubicin attenuated in a dose-dependent manner the increase in numbers of dendritic cells induced by doxorubicin (231 +/- 47, 174 +/- 11, and 100 +/- 16 cells/mm2) after treatment with 6.25, 12.5, and 25 mg of ICRF-187, respectively. Doxorubicin also induced increases in the numbers of T helper lymphocytes and macrophages but not of T cytotoxic/suppressor lymphocytes. These increases were also attenuated by pretreatment with ICRF-187. These data were interpreted as indicating that doxorubicin cardiotoxicity results in the release of substances that initiate immune reactions involving the antigen-presenting cells of the heart and that such reactions are attenuated by pretreatment with ICRF-187.