High levels of histamine can be found in the airways of asthma patients. This study describes the effects of histamine on anti-CD3-induced production of IL-4, IL-5, and IFN-gamma by T cell clones from subjects with allergic asthma and healthy subjects. T cell clones were obtained from bronchoalveolar lavage (BAL) fluid and blood. The number of clones tested, and the percentage of clones in which histamine inhibited or enhanced cytokine production by more than 25%, were as follows: IL-4, 47, 8.5%, and 4.3%; IL-5, 43, 14%, and 30%; and IFN-gamma, 52, 40%, and 15%. Inhibition of IL-5 and IFN-gamma production was reversed by IL-2. The enhancement of IFN-gamma production was associated with an enhancement of both IL-2 production and proliferation. In 21% of the clones a combined effect consisting of inhibition of IFN-gamma production and enhancement of IL-5 production was found. This response was reversed by H2-receptor antagonists and was significantly associated with a histamine-induced increase in intracellular levels of cAMP. The role of cAMP in mediating the histamine effects was supported by the observations that the beta2-agonist salbutamol had effects similar to histamine and that high concentrations of PGE2 mimicked the inhibitory effects of histamine. Clones from BAL fluid and blood showed similar responses, as did clones from patients with asthma and from control subjects. The enhancement of IFN-gamma production by histamine, however, was found only in clones from healthy subjects. The results warrant further investigations on the role of cAMP in the regulation of cytokine production.

We have prepared T-cell clones from bronchoalveolar lavage fluid (BALF) from four healthy, nonsmoking persons and from four patients with allergic asthma. T cells were cloned by direct limiting dilution and with the use of a fluorescent activated cell sorter with an automated cell deposition unit. T-cell clones from the blood (PB) were prepared as well. The cloning efficiencies of T cells from BALF ranged from 3 to 40% and were lower than those obtained from PB T cells (18 to 72%). The cloning conditions generated CD4+ as well as CD8+ clones. The very late antigen-4, VLA-4, was more frequently expressed on CD4+ T-cell clones from BALF than from the blood (P < 0.05). CD8+ clones from BALF were more frequently VLA-1+ than those from blood (P < < 0.01). Mitogen- and monoclonal antibody-driven proliferation of CD4+ clones showed that BALF clones were well responsive to proliferation stimuli similar to those from the blood. Analysis of interleukin-4 production by 10 BALF and 10 PB clones showed large variations between individual CD4+ clones (BALF: range, < 100 to 700 pg/ml; PB: range, < 100 to 1,100 pg/ml), indicating the generation of different types of clones, which was also clear from analysis of interferon-gamma production. The analysis of properties of BALF T-cell clones and their regulation will improve insight into immunologic reactions in the lungs.

We have studied the effects of histamine on the proliferation and the intracellular cyclic adenosine monophosphate (cAMP) levels of T-lymphocyte clones (TLC) generated from bronchoalveolar lavage fluid (BALF) or peripheral blood (PB) from healthy and asthmatic persons. TLC from either compartment and from both groups of donors were heterogeneous in their response to histamine. In BALF-derived TLC, three types of responses were observed: histamine inhibited, stimulated, or did not modulate the anti-CD3-induced proliferation. Histamine directly and dose dependently inhibited the anti-CD3-induced proliferation of six (two asthmatic) of 12 CD4+ BALF TLC, stimulated two BALF TLC (both nonasthmatic), and did not modulate the proliferation of four BALF TLC. The maximal inhibition was 70%, the maximal stimulation 200%, both at 10(-3) M histamine. The stimulation of proliferation was associated with increased interleukin-2 (IL-2) production, whereas the inhibition of proliferation was associated with decreased IL-2 production and downregulation of IL-2 receptor expression. The inhibitory effects could be partly reversed by H2-receptor antagonists and could be mimicked by an H2-receptor agonist. In contrast, the stimulatory effect was not reversed or mimicked by H1 or H2 antagonists or agonists. The majority of CD4+ TLC responded to histamine with a rise in the intracellular cAMP levels. A rise in cAMP, however, was often but not always associated with an inhibition of proliferation. In addition, stimulation of proliferation occurred in the absence of a rise in cAMP. We compared cAMP rises in panels of TLC obtained with high cloning efficiencies from the PB from a healthy person and from an asthmatic person.(ABSTRACT TRUNCATED AT 250 WORDS)

Both increased T cell numbers and their increased activation state have implicated an important role for T cells in chronic inflammatory reactions seen in the airways of (allergic) asthmatics. Airway epithelial cells are frequently exposed to stimuli that cause the release of mediators and the expression of cell adhesion molecules. We have examined whether human airway epithelial cells can activate lung-derived T cells. Clonal lung T cells showed an increased adherence to transformed airway epithelial cells that had been exposed previously for 2 h to human recombinant interferon-gamma (IFN-gamma; 100 U/ml). After an additional 16-24 h of culturing in the absence or presence of epithelial cells, T cells expressed increased levels of both the alpha-chain of the interleukin-2 receptor (IL-2R, CD25) and the transferrin receptor (CD71), both markers of T cell activation. T cells apparently activated by epithelial cells, however, did not produce IFN-gamma or IL-4 nor showed an increased proliferation on the addition of IL-2 (5-50 U/ml). The induced adherence to and the activation of T cells by epithelial cells is mediated largely by CD2 and its ligand lymphocyte functional antigen-3, a pathway known to up- and downregulate T cell functions.