Interleukin-12 (IL-12), a Th1 pro-inflammatory cytokine, is reported to be increased in Sjogren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that over-expresses IL-12 in the lungs. IL-12 transgenics developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjogren patients. Pathologically, lung abnormalities began at around 4 months of age and were characterized by lymphocytic infiltrates around the bronchi, intra-luminal PAS-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (p<0.05 versus wild type littermates) and increased oxidative stress (p<0.01). The pathological and functional abnormalities were accompanied by significant changes in the lung natural killer (NK) cells. NK cells were four-fold higher in IL-12 transgenic than in wild type lungs (20% of all lymphoid cells versus 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of about 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjogren syndrome.