T-cell suppression and contrasuppression induced by histamine H2 and H1 receptor agonists, respectively.

Abstract

The intensity of Lyl T helper and delayed type hypersensitivity effector cell activities is governed, in part, by an interplay between two classes of immunoregulatory T cells: suppressor cells and contrasuppressor cells. We asked whether histamine, at concentrations and duration of exposure that we calculated might be achieved at local sites of inflammation, could activate either or both of these classes of regulatory cells in vitro.To answer this question we used spleen cells from mice treated in vivo with the toleragen trinitrobenzenesulfonic acid as regulators of in vitro generation of primary anti-trinitrophenyl self-cytotoxic T lymphocytes. Under the conditions used, these spleen cells had no major regulatory effects. However, if these cells were preincubated with histamine at 0.1 mM for 30-60 min, suppressor activity was induced, but this occurred inconsistently and with nonstoichiometric results. The use of synthetic histamine agonists revealed that histamine may activate both suppressor and contrasuppressor cell subsets. A histamine HI receptor agonist [2-(2-pyridyl)-ethylamine dihydrochloride] had a propensity to activate contrasuppression, whereas an H2 receptor. agonist (dimaprit) tended to activate suppressor cells. Thus, histamine may have opposing actions that obscure suppression. This duality was shown by treatment ofpyridylethylamine-induced contrasuppressor cells with complement and anti-I-J antibody that kills contrasuppressor cells. This treatment revealed a high level of suppressor cell activity that was not expressed until the opposing contrasuppressor cells were removed. Because histamine is released at local sites of delayed type hypersensitivity, these results indicate that histamine may serve as an inducer of microenvironmental immunomodulation by activating regulatory T cells at sites where immune responses are taking place.

Regulation of Lymphocyte Blastogenesis by Histamine Produced in the Systemper se*

“…The results seem to be consistent with the observation that a histamine HI-receptor agonist, 2-pyridylethylamine, activates contrasuppression, although the Hz-receptor agonist dimaprit activates suppressor cells. 5 ) Those results, together with the results of this study, indicate that histamine may have opposing actions. Endogenous histamine may stimulate lymphocyte blastogenesis via HI-receptors of target cells in the early stages, when production of the amine is low.…”

“…It inhibits immunoglobulin production by B lymphocytes,l) lymphocyte proliferation after mitogenic stimulation 2 • 3 ) or antigenic stimuiation,4) or in vitro production of killer cells. 5 ) The immunosuppressive effect of histamine are probably mediated by activation of suppressor T lymphocytes. 4 -6 ) Almost all of these results were obtained from studies on the effects of histamine added exogenously to each immune system.…”

The impact of anti-inflammatory agents on the outcome of patients with colorectal cancer

“…Activation of histamine receptor-2 on regulatory T-lymphocytes inhibits the cell-mediated immune response (111). Amelioration of this immunosuppressant effect by H2RA use has been shown to subsequently increase tumour infiltration of activated lymphocytes [ Table 2].…”

Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

“…5,6 Early studies had shown that CIM is capable of inhibiting suppressor cell effector function 7 and expansion 8 and that regulatory T cells possess the H2 receptor. [9][10][11] Experimentally, CIM has been shown to enhance a variety of immunologic functions both in vivo and in vitro, including decrease in the relative abundance or function of Treg cells in several studies. [12][13][14] Indeed, Wang J et al 14 reported that the use of CIM as a vaccine adjuvant in mice could induce expression of pro-inflammatory cytokines such as IL-6 and IL-12 and down-regulate expression of anti-inflammatory cytokines, including IL-10 and TGF-b.…”