Activation of neutrophils (PMN) within the airways results in the secretion of a number of products such as reduced oxygen metabolites that could contribute to the inflammatory response associated with asthma. However, mediators of allergy, such as histamine, prostaglandin E2 (PGE2), isoproterenol, and adenosine, may serve to mitigate this inflammation through feedback inhibition of neutrophil function. To test the hypothesis that PMN activation and feedback inhibition mechanisms may be abnormal in asthmatics, we compared both superoxide production and adenosine-induced suppression of superoxide production in 12 matched pairs of asthmatics and control subjects. PMN obtained from asthmatic patients generated significantly more superoxide in response to f-met-leu-phe (fMLP) than controls (2.94 +/- 55 nmol/5 x 10(5) PMN/5 min versus 1.38 +/- 0.35 at 2 x 10(-8) M fMLP and 3.81 +/- 0.68 nmol versus 2.04 +/- 0.45 nmol at 10(-7) M; p less than 0.01 for both). In contrast, the respiratory burst generated by two receptor-independent stimuli, the calcium ionophore A23187 and phorbol myristate acetate, was equivalent between control and asthmatic subjects. At 10(-6) M, 2-chloroadenosine induced a 19.5 +/- 5.1% inhibition of fMLP-stimulated superoxide production in PMN from patients with asthma as compared to 55.6 +/- 24.6% inhibition in PMN from control subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Although clinical responses to allergens have been shown to primarily involve IgE antibodies, there is often no clear correlation between the amount of allergen-specific IgE present in the serum and the nature and severity of allergic symptoms. This observation raises the question of the possible role of non-IgE mediated types of immune responses in this reaction. It is not known to what extent components of T cell-mediated immunity are involved in IgE-mediated reactions but several observations suggest an association between atopic disease and alterations in cellular immune function. These include the frequent association of high serum IgE levels with: (i) several of the primary and acquired immunodeficiencies characterized by partial T cell deficiency; (ii) the defective cell-mediated immunity and resultant recurrent infections seen in the hyper-IgE syndrome; and (iii) the sudden rise in serum IgE levels associated with reduced numbers of suppressor T cells in bone marrow transplant recipients during the acute graft vs host disease. In this review, we will examine the recent evidence suggesting that the T lymphocyte may play a primary role in the pathogenesis of atopic disorders.

We have shown previously that neutrophils (PMNs) from patients with asthma have a more potent stimulated respiratory burst than normals and that their respiratory burst is significantly less suppressed with exposure to 2-chloroadenosine (2-CADO). The present studies investigated the basis of this defect in responsiveness to 2-CADO. PMNs obtained from asthmatics either not on theophylline (minus theophylline) or taking theophylline (plus theophylline) generated significantly more superoxide in response to 2 x 10(-8) M FMLP (2.08 +/- 0.36 nmol/5 x 10(5) PMNs (minus theophylline) (P less than 0.01 compared to controls) vs. 2.16 +/- 0.44 (plus theophylline) (P less than 0.01) as compared to controls (1.05 +/- 0.17 nmol). In the presence of FMLP (2 x 10(-8) M), PMNs from the minus theophylline cohort had less 2-CADO (10(-6) M)-mediated suppression of superoxide generation as compared to controls (38.3 +/- 3.8% vs. 67.1 +/- 3.8%; (P less than 0.001). The plus theophylline group exhibited suppression values similar to controls (64.5 +/- 7.2%). Theophylline, in the presence of a physiological concentration of 2-CADO (0.1 microM) accentuated the suppression of the respiratory burst in normals (74.1 +/- 5.9%, 80.1 +/- 4.9% (P less than 0.02) and 84.7 +/- 3.8% (P less than 0.02) at 0, 10, and 100 microM, respectively). PMNs from asthmatics not taking theophylline demonstrated suppression values of 46.2 +/- 6%, 53.8 +/- 6.6% (P = NS), and 63.2 +/- 7.1% (P less than 0.01), respectively. Resting PMNs from normal controls generated 0.97 +/- 0.20 pmol cAMP/10(7) cells compared to 2.83 +/- 0.75 pmol in the presence of 0.1 microM 2-CADO. The combination of 2-CADO and theophylline (10-100 microM) produced cAMP concentrations not significantly different from that observed with 2-CADO alone. These findings support the existence of a novel cAMP-independent adenosine receptor in PMNs. The specific binding of 10(-8)M 3H-labeled 2-CADO (in delta cpm) was 10,358 +/- 1502 (P less than 0.001 compared to controls), 5468 +/- 843 (NS compared to controls), and 3751 +/- 477 in the plus theophylline group, minus theophylline group, and controls, respectively. Such up-regulation of specific binding may represent the effects of theophylline as shown by the specific binding of [3H]2-CADO in PMNs from normal controls exposed to 10 microM theophylline for 30 min (6013 +/- 969) compared to unexposed PMNs (3768 +/- 656; P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

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