title: Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice.
abstract: BACKGROUND
  The posttraumatic response to traumatic brain injury (TBI) is characterized, in part, by activation of the innate immune response, including the complement system. We have recently shown that mice devoid of a functional alternative pathway of complement activation (factor B-/- mice) are protected from complement-mediated neuroinflammation and neuropathology after TBI. In the present study, we extrapolated this knowledge from studies in genetically engineered mice to a pharmacological approach using a monoclonal anti-factor B antibody. This neutralizing antibody represents a specific and potent inhibitor of the alternative complement pathway in mice.
  
  
  METHODS
  A focal trauma was applied to the left hemisphere of C57BL/6 mice (n = 89) using a standardized electric weight-drop model. Animals were randomly assigned to two treatment groups: (1) Systemic injection of 1 mg monoclonal anti-factor B antibody (mAb 1379) in 400 mul phosphate-buffered saline (PBS) at 1 hour and 24 hours after trauma; (2) Systemic injection of vehicle only (400 mul PBS), as placebo control, at identical time-points after trauma. Sham-operated and untreated mice served as additional negative controls. Evaluation of neurological scores and analysis of brain tissue specimens and serum samples was performed at defined time-points for up to 1 week. Complement activation in serum was assessed by zymosan assay and by murine C5a ELISA. Brain samples were analyzed by immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) histochemistry, and real-time RT-PCR.
  
  
  RESULTS
  The mAb 1379 leads to a significant inhibition of alternative pathway complement activity and to significantly attenuated C5a levels in serum, as compared to head-injured placebo-treated control mice. TBI induced histomorphological signs of neuroinflammation and neuronal apoptosis in the injured brain hemisphere of placebo-treated control mice for up to 7 days. In contrast, the systemic administration of an inhibitory anti-factor B antibody led to a substantial attenuation of cerebral tissue damage and neuronal cell death. In addition, the posttraumatic administration of the mAb 1379 induced a neuroprotective pattern of intracerebral gene expression.
  
  
  CONCLUSIONS
  Inhibition of the alternative complement pathway by posttraumatic administration of a neutralizing anti-factor B antibody appears to represent a new promising avenue for pharmacological attenuation of the complement-mediated neuroinflammatory response after head injury.
authors.affiliation: Department of Trauma and Reconstructive Surgery, Charité University Medical School, Campus Benjamin Franklin, Berlin, Germany. iris.leinhase@charite.de <iris.leinhase@charite.de>
authors.forename: Iris
authors.initials: I
authors.lastname: Leinhase
authors.forename: Michal
authors.initials: M
authors.lastname: Rozanski
authors.forename: Denise
authors.initials: D
authors.lastname: Harhausen
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Thurman
authors.forename: Oliver I
authors.initials: OI
authors.lastname: Schmidt
authors.forename: Amir M
authors.initials: AM
authors.lastname: Hossini
authors.forename: Mohy E
authors.initials: ME
authors.lastname: Taha
authors.forename: Daniel
authors.initials: D
authors.lastname: Rittirsch
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Ertel
authors.forename: Philip F
authors.initials: PF
authors.lastname: Stahel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001930:Brain Injuries / Q000276:immunology* / Q000517:prevention & control*; D011415:Complement Factor B / Q000037:antagonists & inhibitors* / Q000276:immunology*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000911:Antibodies, Monoclonal; D011415:Complement Factor B