阻断LILRB4信号通路逆转多发性骨髓瘤骨损伤的研究

骨损伤是多发性骨髓瘤典型症状，严重影响患者生活质量，因此探讨多发性骨髓瘤骨损伤作用机制、研发新的治疗药物意义重大。本课题前期结果表明：免疫抑制受体LILRB4促进多发性骨髓瘤细胞的免疫逃避，但其在多发性骨髓瘤骨损伤中的作用，未见报道。本研究拟应用lilrb4-Tg-C57BL/KaLwRij和NSG小鼠，分别构建鼠源、人源以及PDX多发性骨髓瘤小鼠模型，查证LILRB4具有促进多发性骨髓瘤骨损伤的功能；拟应用LILRB4阻断型抗体处理各小鼠模型，证实阻断LILRB4信号通路能够抑制多发性骨髓瘤骨损伤；拟应用糖基化位点突变抗体处理消除T细胞、NK细胞和巨噬细胞的小鼠模型，求证单纯阻断LILRB4信号通路能够抑制多发性骨髓瘤骨损伤；拟应用RNA-seq寻找差异表达的细胞因子，拟构建ITIMs突变体细胞，揭示LILRB4促进多发性骨髓瘤骨损伤的作用机制。本研究有望为多发性骨髓瘤患者带来新的疗法。

Bone lesions, as the hallmark of multiple myeloma, severely affect the quality of life for patients with multiple myeloma. Therefore, to explore the mechanism of bone lesions and develop the new therapeutic drug will be significant for patients with multiple myeloma. Our previous results showed that LILRB4, as an immune checkpoint molecule, could mediate the immune escape of multiple myeloma, however, the role of LILRB4 in bone lesions of multiple myeloma has not been reported. In this study, lilrb4-Tg-C57BL/KaLwRij and NSG mice will be used to construct multiple myeloma models of mouse, human and PDX to verify that LILRB4 could mediate the bone lesions of multiple myeloma. The blocking antibody for specific LILRB4 will treat above multiple myeloma models to confirm that blocking LILRB4 signal pathway could inhibit the bone lesion of multiple myeloma. The antibody of glycosylation site mutation will be used to treat all kinds of mouse models in which T cells, NK cells and macrophages will be depleted, which furtherly identify that the bone lesions of multiple myeloma could be inhibited by simple blocking LILRB4 signal pathway. RNA-seq will be used to identify the differentially expressed cytokines, and the ITIMs mutants will be constructed, which will reveal the mechanism by which LILRB4 promotes the bone lesions of multiple myeloma. In brief, our study provides the experimental evidence for the treatment of multiple myeloma with blocking antibody for specific LILRB4, and LILRB4-blocking-Ab will be a potential therapy to patient with multiple myeloma.