Dendritic cells in the hearts of spontaneously hypertensive rats treated with doxorubicin with or without ICRF-187.
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.
Division of Research and Testing, Food and Drug Administration, Laurel, Maryland.
J
J
Zhang
E H
EH
Herman
V J
VJ
Ferrans
D000818:Animals; D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced / Q000453:epidemiology / Q000473:pathology; D007150:Immunohistochemistry; D015994:Incidence; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D011918:Rats, Inbred SHR / Q000033:anatomy & histology*; D011929:Razoxane / Q000008:administration & dosage / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D000911:Antibodies, Monoclonal; D011929:Razoxane; D004317:Doxorubicin