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R Harkness

Publications and source records attributed to R Harkness.

6 recordsLinked to original sources
PubMed1999

Macrophages are a significant source of type 1 cytokines during mycobacterial infection.

T-helper 1 (Th1) cells are believed to be the major producer of the type 1 cytokine interferon-gamma (IFN-gamma) in cell-mediated immunity against intracellular infection. We have investigated the ability of macrophages to release type 1 cytokines and their regulatory mechanisms using both in vivo and in vitro models of pulmonary mycobacterial infection. During pulmonary infection by live Mycobacterium bovis bacilli Calmette-Guérin (BCG) in wild-type mice, lung macrophages released interleukin-12 (IL-12), IFN-gamma, and tumor necrosis factor-alpha (TNF-alpha), and expressed surface activation markers. However, macrophages in infected IL-12(-/-) mice released TNF-alpha but not IFN-gamma and lacked surface activation makers. In freshly isolated lung macrophages from naive IL-2(-/-) mice, mycobacteria alone released TNF-alpha but not IFN-gamma, whereas exogenously added IL-12 alone released a minimum of IFN-gamma. However, these macrophages released large quantities of IFN-gamma upon stimulation with both mycobacteria and IL-12. In contrast, mycobacteria and exogenous IFN-gamma released only a minimum of endogenous IFN-gamma. Endogenous IL-18 (IFN-gamma-inducing factor) played little role in IFN-gamma responses by macrophages stimulated by mycobacteria and IL-12. Our data reveal that macrophages are a significant source of type 1 cytokines during mycobacterial infection and that both IL-12 and intracellular pathogens are required for the release of IFN-gamma but not TNF-alpha. These findings suggest that macrophages regulate cell-mediated immunity by releasing not only IL-12 and TNF-alpha but also IFN-gamma and that full activation of IFN-gamma response in macrophages is tightly regulated.

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PubMed1998

Lack of both types 1 and 2 cytokines, tissue inflammatory responses, and immune protection during pulmonary infection by Mycobacterium bovis bacille Calmette-Guérin in IL-12-deficient mice.

Understanding of key cytokines and the nature of protective immune responses in pulmonary mycobacterial diseases remains a task of paramount importance. In this study, both wild-type (wt) and IL-12-deficient (IL-12(-/-)) mice were infected by airways inoculation of live Mycobacterium bovis bacille Calmette-Guérin (BCG). The type 1 cytokines IL-12, IFN-gamma, and TNF-alpha, but not the type 2 cytokines IL-4 and granulocyte macrophage (GM)-CSF, markedly increased in the lung and peripheral blood of wt mice postinfection, which resulted in the development of intense granulomatous responses and the effective control of mycobacterial infection in the lung. In contrast, IL-12(-/-) mice demonstrated a lack of both types 1 and 2 cytokines in the lung and blood and a severely impaired tissue immune-inflammatory response lacking not only macrophages and neutrophils but CD4 and CD8 T cells and NK cells in the lung throughout the entire course of study. Total lung mononuclear cells isolated from these mice, in contrast to wt mice, had an impaired recall immune response to Ag challenge in vitro. These impaired responses resulted in an uncontrolled local growth and systemic spread of bacilli. Our findings reveal that IL-12 plays an irreplaceable role in the initiation of Th1 responses, and the loss of its function cannot be compensated for by alternative mechanisms in the lung. This cytokine, together with IFN-gamma and TNF-alpha, and granulomatous inflammation are critically required for the effective control of pulmonary mycobacterial infection. Our results also indicate that the absence of type 1 cytokines does not necessarily favor a Th2 response.

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