Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes.
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.
Tuomanen
E I
EI
Laborotory of Microbiology, Rockefeller University, New York, New York 10021.
Saukkonen
K
K
Sande
S
S
Cioffe
C
C
Wright
S D
SD
D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000502:physiology; D000954:Antigens, Surface / Q000276:immunology*; D001424:Bacterial Infections / Q000628:therapy*; D001812:Blood-Brain Barrier; D001929:Brain Edema / Q000517:prevention & control; D018845:CD11 Antigens; D018821:CD18 Antigens; D005260:Female; D007962:Leukocytes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000502:physiology; D008581:Meningitis / Q000628:therapy*; D011817:Rabbits
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D018845:CD11 Antigens; D018821:CD18 Antigens; D008562:Membrane Glycoproteins; D000667:Ampicillin