Novel antagonist antibody to TLR3 blocks poly(I:C)-induced inflammation in vivo and in vitro |
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| Authors: | Bunting Rachel A Duffy Karen E Lamb Roberta J San Mateo Lani R Smalley Karen Raymond Holly Liu Xuesong Petley Ted Fisher Jamie Beck Heena Flavell Richard A Alexopoulou Lena Ward Christine K |
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| Affiliation: | aImmunology Discovery Department, Centocor Research & Development, Inc., Radnor, PA, USA;bBiologics Research, Centocor Research & Development, Inc., Radnor, PA, USA;cDepartment of Immunobiology, Yale University, School of Medicine and Howard Hughes Medical Institute, New Haven, CT, USA;dCentre d’Immunologie de Marseille-Luminy, CNRS-INSERM-Universite de la Mediterranee, Campus de Luminy, Case 906, Marseille Cedex 13288, France;eDepartment of Translational Sciences, MedImmune, Gaithersburg, MD, USA |
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| Abstract: | Toll-like receptor 3 (TLR3) binds and signals in response to dsRNA and poly(I:C), a synthetic double stranded RNA analog. Activation of TLR3 triggers innate responses that may play a protective or detrimental role in viral infections or in immune-mediated inflammatory diseases through amplification of inflammation. Two monoclonal antibodies, CNTO4685 (rat anti-mouse TLR3) and CNTO5429 (CDRs from CNTO4685 grafted onto a mouse IgG1 scaffold) were generated and characterized. These mAbs bind the extracellular domain of mouse TLR3, inhibit poly(I:C)-induced activation of HEK293T cells transfected with mTLR3, and reduce poly(I:C)-induced production of CCL2 and CXCL10 by primary mouse embryonic fibroblasts. CNTO5429 decreased serum IL-6 and TNFα levels post-intraperitoneal poly(I:C) administration, demonstrating in vivo activity. In summary, specific anti-mTLR3 mAbs have been generated to assess TLR3 antagonism in mouse models of inflammation. |
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| Keywords: | TLR3 Poly(I:C) Monoclonal antibody |
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