Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes.

Abstract

We tested if specific inhibition of recruitment of leukocytes across the blood brain barrier from the vascular compartment to the cerebrospinal fluid (CSF) space reduced tissue damage and improved the outcome of infection in a rabbit model of experimental meningitis. The CD11/CD18 complex of receptors on leukocytes promotes adhesion of these cells to endothelia, a process required for egress of cells into the extravascular space. Intravenous injection of the anti-CD18 mAb IB4 effectively blocked the development of leukocytosis in the CSF of animals challenged intracisternally with living bacteria, bacterial endotoxin, or bacterial cell wall. This effect was associated with protection from blood brain barrier injury as measured by exclusion of serum proteins from CSF in mAb-treated animals. The densities of bacteria in CSF and the degrees of bacterial killing due to ampicillin were not affected by the antibody. Animals receiving the antibody experienced a delay in the development of bacteremia and a significantly reduced inflammatory response during ampicillin-induced bacterial killing. Therapy with mAb IB4 prevented development of brain edema and death in animals challenged with lethal doses of Streptococcus pneumoniae. These studies indicate that the major mechanism of leukocyte migration across the blood brain barrier involves the CD11/CD18 receptors and that inflammatory leukocytes recruited by this mechanism are a major cause of blood brain barrier injury and cerebral edema during meningitis.

Concepts and Mechanisms: Crossing Host Barriers

“…Although neutrophils are critically important to fight against bacterial sepsis, depletion of peripheral neutrophils in a murine hematogenous model of GBS meningitis prolonged survival, decreased bacterial CNS load, and decreased BBB leakage in GBS-infected mice (Banerjee et al 2011). Correspondingly, prevention of leukocyte infiltration into the CNS using anti-CD18 antibody has been shown to improve pneumococcal and HiB meningitis outcomes (Tuomanen et al 1989;Saez-Llorens et al 1991).…”

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

“…More recently, it was shown that S. pneumoniae may also be recognized by inflammasomes that are dependent upon the adaptor molecule ASC (16)(17)(18)(19). Together, these pathways initiate immune activation and lead to production of inflammatory cytokines and chemokines that subsequently mediate the recruitment of leukocytes to the site of infection (20)(21)(22)(23)(24)(25)(26). However, when this occurs within the brain, the ensuing inflammatory response is argued to ultimately cause neuronal damage and/ or death (9,10).…”

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

“…TLR activation results in MyD88-dependent production of high levels of cytokines and chemokines (6), which facilitates the accumulation of large amounts of blood-borne leukocytes (predominantly neutrophils) inside the CSF. The resultant excessive neutrophilic inflammation causes collateral damage to the brain, thus contributing substantially to the unfavorable outcome of meningitis (7,8).…”