Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in miceReport as inadecuate

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 - Download this document for free, or read online. Document in PDF available to download.

Journal of Neuroinflammation

, 4:13

First Online: 02 May 2007Received: 19 March 2007Accepted: 02 May 2007


BackgroundThe 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.

MethodsA 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 μl phosphate-buffered saline PBS at 1 hour and 24 hours after trauma; 2 Systemic injection of vehicle only 400 μl 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.

ResultsThe 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.

ConclusionInhibition 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.

AbbreviationsCNSCentral nervous system



ELISAenzyme-linked immunosorbent assay

GFAPglial fibrillary acidic protein

NeuNneuron-specific nuclear protein

OPDo-phenylenediamine dihydrochloride

PBSphosphate-buffered saline

real-time RT-PCRreal-time reverse transcriptase polymerase chain reaction

RTroom temperature

SDS-PAGEsodium dodecyl sulfate-polyacrylamide gel electrophoresis

TBItraumatic brain injury

TdTterminal deoxynucleotidyl transferase

TUNELterminal deoxynucleotidyl transferase biotin-dUTP nick end labeling.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-2094-4-13 contains supplementary material, which is available to authorized users.

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Author: Iris Leinhase - Michal Rozanski - Denise Harhausen - Joshua M Thurman - Oliver I Schmidt - Amir M Hossini - Mohy E Taha


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