Inhibition of Guinea‐pig Lymphocyte Activation by Histamine and Histamine Analogues

Abstract

I The incorporation of [3H]-thymidine into guinea-pig lymphocytes stimulated by a plant lectin (concanavalin A), soluble antigen (tuberculin (P.P.D.)) and syngeneic hepatoma cells, was partially inhibited (50%) by histamine in vitro. 2 The effect of histamine on both mitogen and antigen dose-response curves suggests a non-competitive, probably physiological antagonism.3 The inhibitory dose range of histamine lay between 10 nm and 30 AM with an ID50 of approximately 400 nM. 4 The potency order for histamine analogues for the inhibition of lymphocyte activation was histamine > 4-methylhistamine > 2-methylhistamine > 3-methylhistamine. This is in accord with the mediation of the response through an H2-receptor. 5 H2-receptor antagonists reversed the inhibitory effect of histamine in a dose-related manner, but both metiamide and burimamide, in high concentrations, augmented lymphocyte activation in their own right. This precluded the determination of affinity constants and made it impossible to state with certainty that the inhibition of lymphocyte activation by histamine was mediated by an H12-receptor.

INHIBITION OF LYMPHOCYTE PROLIFERATION BY HISTAMINE AND RELATED COMPOUNDS NOT MEDIATED VIA H1‐ OR H2‐ RECEPTORS

“…We have confirmed the finding (Wang & Zweiman, 1978;Beets & Dale, 1979;Brostoff et al, 1980;Ogden & Hill, 1980) The following five findings from the data summarized in Table 1 were found to be inconsistent with the view that the inhibitory effects of histamine-related compounds on lymphocyte proliferation were mediated via H,-or H2-receptors. Firstly, N-3-methylhistamine, which is inactive on conventional histamine receptors (Ganellin, 1980), was as active as histamine in inhibiting lymphocyte transformation in the same concentration range (10 4-10-3M).…”

“…In the present experiments, the effect of cimetidine or metiamide on histamineinduced inhibition was equivocal (data not shown). These H2-receptor antagonists have been found to augment mitogenesis in the absence of exogenous histamine (Beets & Dale, 1979;Gifford, Stephen, Hatfield & Schmidtke, 1980) and this effect complicates the interpretation of the reversal of inhibition by histamine-related compounds. Nevertheless, the possibility remains that human mononuclear cells bear H2-receptors concerned with other functional activities, such as the inhibition of synthesis of complement components (Lappin & Whaley, 1980) and the generation of soluble factor(s) that suppress lymphokine production (Rocklin, 1977).…”

“…However, this classification has been questioned by workers who found discrepancies between H2-receptor stimulating activity and inhibition of lymphocyte transformation (Beets & Dale, 1979;Vickers, Arlington, Jones, Martin & Melvin, 1980;Brostoff et al, 1980). In the present study we have reinvestigated the nature of the receptor involved in lymphocyte transformation by examining a group of chemical analogues of histamine.…”

“…Histamine has been shown to affect many aspects of lymphocyte functions, including proliferation (Wang & Zweiman, 1978;Beets & Dale, 1979;Brostoff, Pack & Lydyard, 1980;Ogden & Hill, 1980) and lymphokine production (Rocklin, 1976;Rocklin, Breard, Gupta, Good & Melmon, 1980), and this has led to the suggestion that endogenous histamine may act as an immunomodulator via an H2-receptor (Busse, 1979). However, this classification has been questioned by workers who found discrepancies between H2-receptor stimulating activity and inhibition of lymphocyte transformation (Beets & Dale, 1979;Vickers, Arlington, Jones, Martin & Melvin, 1980;Brostoff et al, 1980).…”

A comparison of dimaprit, nordimaprit, methylamine and chloroquine as inhibitors of mitogen‐induced lymphocyte activation

“…These include the autacoid, histamine, (Wang & Zweiman, 1978;Beets & Dale, 1979) histamine analogues (Vickers et al, 1980;Gordon et al, 1981) and chloroquine and its congeners (Hurvitz & Hirschhorn, 1965;Trist & Weatherall, 1981). It has been suggested that histamine produces its effects by an action on an H2-receptor (Wang & Zweiman, 1978), though adequate pharmacological evidence for this is difficult to obtain (Beets & Dale, 1979).…”