title: Characterization, epitope identification and mechanisms of the anti-septic capacity of monoclonal antibodies against macrophage migration inhibitory factor.
abstract: Sepsis is characterized by uncontrolled inflammatory responses. Macrophage migration inhibitory factor (MIF) has been shown to play an important role in the progression of sepsis thus is a potential therapeutic target. The aim of this study is to produce IgG anti-MIF monoclonal antibodies (mAbs) with anti-septic abilities in vivo and to determine mechanisms of their function. We generated 8 IgG anti-MIF mAbs with high specificity and 3 of them showed potent protective abilities in murine lethal peritonitis induced by cecal ligation and puncture (CLP). One anti-MIF mAb, F11, showed 100% protection within 72 h after sepsis induction and 72% mice treated with this mAb survived up to 84 h with reduced lung and kidney pathology. F11 treatment also reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels in septic mice. We further found that all 8 anti-MIF mAbs recognized the same epitope located in the amino acid residue 1-20 region of the N terminus of the MIF protein. Three of the mAbs, F11 in particular, inhibited tautomerase activity in association with their protective effect on CLP mice. Thus, we have produced anti-MIF mAbs that protected mice from CLP-induced sepsis by recognizing the same epitope domains in MIF. These mAbs are promising candidates for further development of therapeutics against inflammatory diseases.
authors.affiliation: Department of Clinical Biochemistry, Laboratory Sciences, the Third Military Medical University, Chongqing, Gaotanyan Street 30, Shapingba District, Chongqing 400038, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Zeng
authors.forename: Sha
authors.initials: S
authors.lastname: Chen
authors.forename: Zhujun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Weijing
authors.initials: W
authors.lastname: Yi
authors.forename: Hongtao
authors.initials: H
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.forename: Shuhui
authors.initials: S
authors.lastname: Li
authors.forename: Chuanmin
authors.initials: C
authors.lastname: Hu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D002432:Cecum / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D018604:Epitope Mapping; D000939:Epitopes / Q000032:analysis; D005260:Female; D007074:Immunoglobulin G / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D015850:Interleukin-6; D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha