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Longitudinal Tracking of Cytokines after Acute Exposure to Tuberculosis: Association of Distinct Cytokine Patterns with Protection and Disease Development

Department of Pathology and Microbiology, The Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan,¹ Masoomeen General Hospital, Musa Lane, Kharadar, Karachi, Pakistan²

Received 17 July 2007/ Returned for modification 19 September 2007/ Accepted 2 October 2007

Household contacts (HCs) of patients with tuberculosis (TB) are at higher risk of infection as well as the development of active disease. Longitudinal tracking of antigen-specific cytokines after acute exposure may significantly advance our understanding of the dynamic changes in cytokine patterns associated with disease establishment. To achieve this objective, we carried out a prospective cohort study with healthy HCs after exposure to TB. The patterns of cytokines (gamma interferon [IFN-] and interleukin 10 [IL-10]) in response to mycobacterial antigens (culture filtrate [CF] proteins) and nonspecific mitogens (phytohemagglutinin [PHA] and lipopolysaccharide [LPS]) were assessed at 0, 6, 12, and 24 months after exposure. Seven of 109 (6.4%) HCs developed active disease. Six of the seven individuals were females, and active disease developed between 12 and 15 months after exposure in 5/20 families. The most significant findings were the exponential increases (1,000-fold) in both the CF protein- and the PHA- or LPS-induced IFN-/IL-10 ratio in healthy HCs (n = 26), which peaked at 12 months, compared to the levels in HCs who developed disease (n = 7), in whom relatively flat responses were observed during the 24-month period. Linear trends for 0 to 12 and 0 to 24 months for the CF protein-induced IFN-/IL-10 ratio showed significant differences between the two groups, as determined by the use of the Mantel extension test for ² analysis (odds ratio = 0.45; 95% confidence interval = 0.295 to 0.685; P = 0.0002). Our results strongly suggest that the magnitude of the IFN-/IL-10 ratio at 12 months after exposure may be a critical determinant in the resolution of infection. These studies provide new insights into the cytokine responses associated with disease establishment or the resolution of infection after natural exposure to TB and have implications for TB control programs as well vaccine efficacy studies.

Published ahead of print on 10 October 2007.