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Protective effect of anti‐TLR3 monoclonal antibody in Poly(I:C)/D‐galactosamine induced mouse sepsis model
Author(s) -
Li Chen,
Guzman Victor,
Lee Iris,
Liang Yanbin
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1120.6
Subject(s) - tlr3 , apoptosis , microbiology and biotechnology , monoclonal antibody , inflammation , receptor , tumor necrosis factor alpha , biology , chemistry , antibody , immunology , biochemistry , toll like receptor , innate immune system
Activation of toll‐like receptor 3 (TLR3) by foreign and endogenous ligands including viral dsRNA, bacterial RNA, mitochondrial RNA, and endogenous necrotic cell mRNA could trigger both apoptosis and inflammatory pathways that lead to disease development. Therefore, the hypothesis was that the blockade of TLR3 activity could be an approach to treat apoptosis and inflammation related disorders. First, anti‐TLR3 monoclonal antibodies were generated using standard hybridoma technology and then screened by Octet binding affinity assay. The antibody, R11H8, which specifically bound to mouse TLR3 receptor with Kd 2.97×10 −10 M affinity was identified and expanded for cell‐based functional assays. Using TLR3‐overexpressing stable cell line, R11H8 dose‐dependently blocked poly(I:C)‐induced IL‐8 release (IC50 = 60nM). The mouse sepsis model was induced by administration of D‐galactosamine and poly(I:C). In this model, D‐galactosamine is a hepatotoxin which function as a sepsis sensitizer, and poly(I:C) is a sepsis‐inducing molecule that mimics dsRNA and activates TLR3. R11H8 (1 mg/mouse) was intraperitoneally injected into mice one day before Poly (I:C)/D‐galactosamine induction. Three days after sepsis induction, mice that did not receive the antibody were dead, whereas all of the mice in anti‐TLR3 treated group survived. The result confirmed that the blockade of TLR3 receptor activity could diminish the pathogenesis of dsRNA induced sepsis. The generation of anti‐TLR3 mAb, R11H8, provided a powerful tool for us to better understand the role of TLR3 in the inflammation and apoptosis related disease development.