Pulmonary eosinophilic granuloma is a disorder caused by localized collections of proliferating histiocytes in the lung. Little is known about its etiology except that the majority (58 to 97%) of patients are current or ex-smokers, making the potential etiologic role of tobacco products an important area for research. Tobacco glycoprotein (TGP) is a potent immunostimulator that has been isolated from cigarette smoke. TGP-specific lymphocyte proliferation, and cytokine production in vitro, were measured in three patients with pulmonary eosinophilic granuloma in remission and in three closely matched normal subjects with similar smoking histories. One patient with eosinophilic granuloma of bone and a matched control subject were also studied. Peripheral blood mononuclear cells were cultured with TGP, the recall antigen streptokinase (SK), and the mitogen concanavalin A (Con A). All three of the patients with pulmonary eosinophilic granuloma exhibited significant decreases in lymphocyte stimulation to TGP, despite normal responses to SK and Con A. In contrast, the response of the patient with eosinophilic granuloma of bone was higher than her matched control. The mean responses of the patients with pulmonary eosinophilic granuloma to TGP was significantly lower than the mean of nondiseased smokers or of normal nonsmokers. Twenty-four-hour culture supernatants were collected and assayed for cytokine levels (IL-1, IL-2, and IL-6). TGP-stimulated IL-2 production was significantly lower in the patients with pulmonary eosinophilic granuloma than in the normal subjects, confirming the reduced T-cell proliferative response.(ABSTRACT TRUNCATED AT 250 WORDS)