Department of Clinical Biochemistry, Laboratory Sciences, the Third Military Medical University, Chongqing, Gaotanyan Street 30, Shapingba District, Chongqing 400038, PR China.
Int Immunopharmacol. 2011 Sep;11(9):1333-40. doi: 10.1016/j.intimp.2011.04.017. Epub 2011 May 13.
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.
脓毒症的特征是不受控制的炎症反应。已经表明巨噬细胞移动抑制因子（MIF）在脓毒症的进展中发挥重要作用，因此是一个潜在的治疗靶点。本研究的目的是产生具有体内抗败血症能力的 IgG 抗 MIF 单克隆抗体（mAbs），并确定其功能机制。我们产生了 8 种具有高特异性的 IgG 抗 MIF mAbs，其中 3 种在盲肠结扎和穿刺（CLP）诱导的小鼠致死性腹膜炎中显示出强大的保护能力。一种抗 MIF mAb，F11，在脓毒症诱导后 72 小时内提供了 100%的保护，并且用该 mAb 治疗的 72%的小鼠存活至 84 小时，肺和肾病理减少。F11 治疗还降低了脓毒症小鼠中肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的水平。我们进一步发现，所有 8 种抗 MIF mAb 都识别位于 MIF 蛋白 N 端氨基酸残基 1-20 区域的相同表位。其中 3 种 mAb，特别是 F11，在与 CLP 小鼠的保护作用相关的情况下抑制了互变异构酶活性。因此，我们已经产生了抗 MIF mAb，通过识别 MIF 中的相同表位域来保护小鼠免受 CLP 诱导的败血症。这些 mAb 是针对炎症性疾病进一步开发治疗方法的有前途的候选药物。
