Abstract
The in vitro effect of histamine and its antagonists, cimetidine and clemastine fumarate, on natural killer (NK) and antibody-dependent cellular Cytotoxicity (ADCC) activities of human lymphocytes was investigated. The histamine 1 (H1) antagonist, clemastine fumarate, and the histamine 2 (H2) antagonist, cimetidine, but not histamine alone, inhibited the NK and ADCC activities of lymphocytes when added directly to the mixture of effector and target cells in a 51Cr-release assay. This inhibition was proportional to the concentration of drugs added and was observed at various effector to target ratios against several targets. H1 and H2 antagonists also inhibited NK activities of T cells as well as Percoll-separated, NK-enriched effector cells. The inhibition was significantly reversed by histamine. In target binding assays, clemastine fumarate and cimetidine also decreased the target binding capacity of effector lymphocytes. Further, PBL precultured with histamine (10 −3–10 −4 M) for 24 hr showed a significant decrease in their NK and ADCC activities. In coculture experiments, PBL precultured with histamine suppressed the NK activity of normal autologous effector lymphocytes. PBL precultured with histamine showed an increased number of OKT8 + cells, as estimated using monoclonal antibodies. The suppression of Cytotoxicity was not due to either direct toxicity, steric hindrance, crowding, or cell death, but by functionally viable suppressor cells. An immunoregulatory role for histamine in NK and ADCC reactions is proposed.
Highlights
We and our co-workers have previously demonstrated that unstimulated, cultured human peripheral blood lymphocytes (PBL)4 can develop suppressor cell activities against lymphocyte transformation, polyclonal B-cell activation, and natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) reactions, as a possible consequence of an autologous mixed-lymphocyte culture reaction (l-3)
The results indicate that lymphocytes precultured with histamine demonstrated a significant decrease in their NK and ADCC activities and were able to suppress the NK activity of autologous effector cells in coculture experiments
The results suggest that histamine antagonists inhibit or block NK and ADCC reactions of lymphocytes
Summary
We and our co-workers have previously demonstrated that unstimulated, cultured human peripheral blood lymphocytes (PBL) can develop suppressor cell activities against lymphocyte transformation, polyclonal B-cell activation, and natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) reactions, as a possible consequence of an autologous mixed-lymphocyte culture reaction (l-3). Other studies on T-lymphocyte subpopulations have shown that T cells bearing Fc receptors for human IgG (Ty) mediate both NK and ADCC activities [6, 7] and exhibit suppressive effects on various lymphocyte reactions [8,9,10]. In vitro investigations showed that histamine inhibits cell-mediated cytotoxicity, lymphocyte proliferative responses to mitogens and soluble antigens, lymphokine production, and the mixed-lymphocyte reaction ( 11- 15). Our interest in immunoregulation of natural and antibody-dependent cellular cytotoxicity of human lymphocytes led us to investigate the effect of histamine and histamine antagonists on NK and ADCC activities of human lymphocytes. An immunoregulatory role of histamine in cellular cytotoxic reactions is proposed
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