CYTOKINE MODULATION ALTERS PULMONARY CLEARANCE OF RHODOCOCCUS-EQUI AND DEVELOPMENT OF GRANULOMATOUS PNEUMONIA

Rhodococcus equi, a facultative intracellular bacterium, causes chroni c, often fatal granulomatous pneumonia in young horses and in humans w ith AIDS. The inability of host alveolar macrophages to kill intracell ular R. equi results in the development of granulomas and progressive loss of pulmonary parenchyma. Clearance of the organism from the lung requires functional CD4(+) T cells. The purpose of this study was to i dentify the cytokine effector mechanisms that mediate clearance of R. equi from the lung. Mice were treated with monoclonal antibodies (MAbs ) to either gamma interferon (IFN-gamma) or interleukin-4 (IL-4) to de termine the role of endogenous production of these cytokines in pulmon ary clearance of R. equi. Mice treated with an anti-IL-4 or isotype co ntrol MAb cleared R. equi by 21 days postinfection and expressed incre ased levels of IFN-gamma mRNA, as detected by transcriptional analysis of bronchial lymph node CD4(+) T cells. In contrast, mice treated wit h the anti-IFN-gamma MAb failed to express detectable IFN-gamma mRNA, expressed increased levels of IL-4 mRNA, failed to clear pulmonary inf ection, and developed pulmonary granulomas with large numbers of eosin ophils. The enhancement of IL-4 mRNA expression and a predominance of eosinophils in pulmonary lesions of anti-IFN-gamma-treated mice sugges t that a nonprotective Th2 response is involved in disease pathogenesi s. The association of increased bronchial lymph node CD4(+) T-cell IFN -gamma mRNA expression with pulmonary clearance of R. equi suggests th at a Th1 response is protective.