Development of therapeutic RANKL vaccination approach against inflammatory alveolar-bone-destruction

核因子κ B受体激活因子配体（RANKL）是一种膜结合型细胞因子，在破骨细胞的分化和活化中起重要作用。我们建立了一种新的治疗方法，对病理性骨吸收使用RANKL疫苗。RANKL疫苗的施用在小鼠中诱导快速抗RANKL抗体诱导，并有效抑制关节炎模型小鼠中的骨破坏，SKG小鼠由Shimon Sakaguchi博士（京都大学）建立，本文报道的研究结果表明，靶向RANKL的治疗性疫苗方法可用于抑制病理性骨丢失状况如类风湿性关节炎（RA）和骨质疏松症中的骨破坏。由于未能成功建立牙周病模型，因此无法观察疫苗对牙周病模型的影响。虽然我们这次未能成功，但该疫苗对小鼠RA模型（一种炎性骨破坏模型）的作用表明，该疫苗对牙周病骨破坏具有抑制作用的可能性，与其他针对病理抗原的治疗性重组蛋白如单克隆抗体、可溶性受体或其他拮抗剂相比，疫苗需要较小剂量的蛋白质才能产生效果。一旦通过疫苗接种建立了免疫应答，就很容易通过疫苗加强来维持。骨破坏的基础病理学在骨相关疾病如RA、牙周炎和骨转移中是相似的。这种RANKL疫苗接种将是治疗任何类型病理性骨破坏的新方法。

Receptor activator of NF-kB ligand (RANKL) is a membrane-bound cytokine, which plays an important role in osteoclast differentiation and activation. We established a novel therapeutic approach against pathological bone resorption using RANKL vaccine. Administration of RANKL vaccine induced a rapid anti-RANKL antibody induction in mice, and efficiently suppressed bone destruction in arthritis model mice, SKG mice established by Dr Shimon Sakaguchi (Kyoto Univ.), and bone loss in ovariectomized mice.The results of the studies reported here demonstrate that a therapeutic vaccine approach, targeting RANKL, is useful to inhibit bone destruction in pathological bone-loss conditions such as rheumatoid arthritis (RA) and osteoporosis. We could not show the effects of the vaccine on periodontal disease-model since we failed to establish the model. Although we could not make it this time, the effects of the vaccine on mice RA-model, a kind of the inflammatory bone destruction model, suggest the possibility for the inhibitory effects on bone destruction in periodontal disease.Compared with the use of other therapeutic recombinant proteins against pathological antigens such as monoclonal antibodies, soluble receptor or other antagonists, a vaccine needs smaller doses of protein to induce its affect. Once the immune response is established by vaccination, it is easily maintained by boosting with the vaccine. The underlying pathology of bone destruction is similar in bone-related diseases such as RA, periodontitis and bone metastasis. This RANKL vaccination would be a novel approach to any kind of pathological bone destruction.