Reversible opening of the blood-brain barrier by anti-bacterial antibodies.
The leukocyte adhesion molecule CR3 (CD11b/CD18, Mac-1) promotes leukocyte transmigration into tissues by engaging an unknown cognate ligand on the surface of vascular endothelial cells. Filamentous hemagglutinin (FHA), an adhesin of the bacterium Bordetella pertussis, binds to CR3. We hypothesized that FHA mimics the native ligand for the CR3 integrin on endothelial cells and predicted that anti-FHA antibodies should bind to endothelial cells, interfere with leukocyte recruitment, and induce endothelial permeability. Anti-FHA monoclonal antibodies bound to cerebral microvessels in sections from human brain and upon intravenous injection into rabbits. Antibody binding correlated with the ability to recognize two polypeptides in extracts of human cerebral vessels that were also bound by CD18. In vivo, antibody binding not only interfered with transmigration of leukocytes into cerebrospinal fluid but also induced a dose-dependent reversible increase in blood-brain barrier permeability sufficient to improve delivery of intravenously administered therapeutic agents to brain parenchyma.
Tuomanen
E I
EI
Laboratory of Molecular Infectious Diseases, Rockefeller University, New York, NY 10021.
Prasad
S M
SM
George
J S
JS
Hoepelman
A I
AI
Ibsen
P
P
Heron
I
I
Starzyk
R M
RM
D000818:Animals; D000907:Antibodies, Bacterial / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001886:Bordetella pertussis / Q000276:immunology*; D018821:CD18 Antigens; D002196:Capillaries / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000098:blood supply / Q000502:physiology*; D002560:Cerebrovascular Circulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D011817:Rabbits; D016028:Receptors, Leukocyte-Adhesion / Q000378:metabolism
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D016028:Receptors, Leukocyte-Adhesion