Suppression of Macrophage Activation with CNI-1493 Increases Survival in Infant Rats with Systemic Haemophilus influenzae Infection

Abstract

CNI-1493, a potent macrophage deactivator, was used to treat infant rats systemically infected with Haemophilus influenzae type b (Hib). CNI-1493 was injected 1 h prior to bacterial inoculation and 24 h later and resulted in a 75 percent increased rate of survival compared to that for untreated controls. The effect of CNI-1493 on the inflammatory response was studied by immunohistochemical detection of individual tumor necrosis factor alpha (TNF-α)-, interleukin 1 beta (IL-1β)-, and gamma interferon (IFN-γ)-producing cells in the spleen. A significant reduction of the incidence of TNF-α- and IL-1β-expressing cells was found for CNI-1493-treated animals. IFN-γ expression was not suppressed by CNI-1493, indicating that cytokine inhibition was specific in macrophages. CNI-1493 significantly reduced the number of infiltrating granulocytes in the brain from that for controls. This study provides evidence that CNI-1493 protects against lethal Hib infection by deactivating the inflammatory cascade in infant rats.

Inhibition of meningitis-associated neutrophil apoptosis by TNF-α depends on functional PI3-kinase in monocytes

“…Thus, monocytes play a pivotal role in the protection of neutrophils from apoptosis. In keeping with our results, it has been shown in a model of experimental meningitis caused by H. influenzae that deactivation of macrophages results in reduction of the number of neutrophils in the brain, the effect being associated with protection against lethality [28]. Our results imply that the antiapoptotic effect on neutrophils induced by TNF-␣ depends on functional PI3K in monocytes, whereas PI3K is dispensable in neutrophils themselves.…”

Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection

“…The infant rat model of hematogenous meningitis has been widely used to investigate the influence of bacterial virulence factors, host protective factors, and vaccine candidates on invasive disease caused by H. influenzae (21,26,39,61,66). Few investigations have examined the roles of hemoglobin and hemoglobin-haptoglobin binding proteins encoded by H. influenzae or by other bacterial species in proliferation in vivo and in pathogenesis (10,28,38,62).…”

Essential Neuroscience in Immunology

“…We had developed a cytokine blocking molecule (CNI-1493) (15–18) and were studying its effects in the brain of animals with stroke, when we made the striking observation that production of TNF and other cytokines in the reticuloendothelial system was inhibited by the presence of CNI-1493 in the brain (16). Accordingly, we postulated that signals descending from the brain in the vagus nerve comprise a previously unknown motor arc in an “inflammatory reflex”, completing a sensory arc activated by the presence of IL-1 and other cytokines (19).…”