Mechanisms of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD)-induced humoral immune suppression: evidence of primary defect in T-cell regulation.
The antibody response of C57B1/6 mice to sheep erythrocytes (SRBCs), a macrophage and T-cell-dependent antigen, is highly sensitive to suppression by 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), a major immunotoxic contaminant of pentachlorophenol. The present studies have used several in vivo approaches to characterize the humoral immune suppression produced by an acute oral exposure to HpCDD and to assess the potential cellular defects responsible for the suppression. Administration of HpCDD at various times prior to or following antigen challenge indicated that HpCDD induced rapid yet prolonged suppression of the antibody response. Timing studies also suggested that initial processing of antigen by the macrophage and antibody production by the mature plasma cell were resistant to HpCDD. The demonstration that antibody responses could not be improved by either increasing or decreasing the antigen dose indicated that the effects of HpCDD were not related to the level of antigenic stimulation per se. In addition, there was no evidence for a shift in the kinetics of the antibody response of HpCDD-treated mice at any antigen dose that might have reflected a delay in the development of the response. The dose-response effects of HpCDD on antibody responses to T-helper-cell-dependent (SRBC) and T-helper-cell-independent type 1 (TNP-LPS) and type 2 (DNP-Ficoll) antigens indicated that sensitivity to HpCDD-induced suppression directly correlated with the sensitivity of the response to T-cell regulation. Nonspecific activation of T-amplifier cells with concanavalin A was capable of reconstituting the depressed antibody response of mice treated with 100 micrograms/kg HpCDD but not of mice treated with 500 micrograms/kg HpCDD, further suggesting that regulatory T cells are most sensitive to HpCDD. Definitive evidence for the role of regulatory T cells in mediating HpCDD-induced suppression of the antibody response was obtained in studies using congenitally T-cell-deficient nude (nu/nu) mice. The antibody response to DNP-Ficoll was was assayed since the anti-DNP response proceeds in the absence of T-helper cells in nu/nu mice yet the response can be modulated by changes in the activity of T-amplifier and T-suppressor cells present in nu/+ mice. Results of these studies showed that nu/nu mice were significantly more resistant to the immunosuppressive effects of HpCDD as compared with their nu/+ littermates.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D003208:Concanavalin A / Q000494:pharmacology; D004147:Dioxins / Q000633:toxicity*; D005260:Female; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D013934:Thymectomy; D013997:Time Factors
D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D003208:Concanavalin A; C046839:1,2,3,4,6,7,8-heptachlorodibenzodioxin