MIF活性区域靶向抗体制备及其抗脓毒症机制研究

The high mortality of sepsi is severely threatening human health all the time. Therefore, it is of vital importance to seek related factors of sepsis. Macrophage migration inhibitory factor (MIF) is an important kind of pro-inflammatory cytokine released by macrophage, T cell and pituitary, which promote the body's immune response and inflammatory reaction through many ways. Studies show that the overexpression of MIF has a close relationship with sepsis and that the anti-MIF antibody has an obvious protection effect on sepsis model mice. The active region of the trimer structure formed by MIF monomer is a key site of MIF Proinflammatory effect. Anti-MIF antibody is considerded as a potential treatment of sepsis for its high specificity and small side effect. In the previous experiment, we got antibody F11 which specifically binds to MIF activity area, showing significant anti-sepsis effect. Determining the epitope recognized by the antibody F11 contributes to identify the functional epitope of MIF activity region,which provide a more convenient way to preparate antibodies targeting the action domain of MIF. Therefore, we intend to predict MIF functional epitope by computer homology modeling and molecular modeling technique and preparate the targeting antibodies.At the same time,we intend to study the possible mechanisms of MIF antibody inhibiting macrophage to release inflammatory cytokines TNF-α and IL-6, to lay foundations for further development of sepsis antibody drugs.

脓毒症高死亡率一直威胁着人类健康，发现新的相关因子对于研究有效的脓毒症治疗手段具有重要意义。巨噬细胞移动抑制因子是由巨噬细胞、活化T淋巴细胞及脑垂体释放的重要促炎症因子，其表达水平与脓毒症严重程度密切相关，其三聚体结构形成的活性区域是MIF发挥促炎作用的关键位点。抗MIF抗体因为其特异性高、副作用小的特点，作为脓毒症治疗手段具有良好的发展前景。我们在前期试验中得到的抗体F11特异性地结合于MIF活性区域，表现出显著的抗脓毒症作用，确定抗体F11识别的表位有助于发现MIF活性区域功能性表位，为批量生产具有中和作用的MIF靶向抗体提供更便捷的途径。因此本研究拟通过计算机同源建模及分子模拟技术预测MIF活性区域功能性表位并制备具有中和活性的MIF活性区域靶向抗体，同时初步探讨MIF抑制巨噬细胞释放炎症因子TNF-α、IL- 6的可能机制，为进一步研制脓毒症抗体药物奠定基础。