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

NF-kB配体受体激活因子（Receptor activator of NF-kB ligand， RANKL）是一种膜结合的细胞因子，在破骨细胞的分化和活化中起重要作用。我们建立了一种利用RANKL疫苗对抗病理性骨吸收的新方法。RANKL疫苗在小鼠中诱导了快速的抗RANKL抗体诱导，并有效地抑制了关节炎模型小鼠（京都大学Shimon Sakaguchi博士建立的SKG小鼠）的骨破坏和去卵巢小鼠的骨质流失。本文报道的研究结果表明，针对RANKL的治疗性疫苗方法有助于抑制病理性骨质流失疾病（如类风湿关节炎（RA）和骨质疏松症）的骨破坏。我们不能显示疫苗对牙周病的影响，因为我们没有建立模型。虽然我们这次未能成功，但疫苗对小鼠ra -模型（一种炎症性骨破坏模型）的影响提示了其对牙周病骨破坏的抑制作用的可能性。与使用其他治疗性重组蛋白对抗病理抗原（如单克隆抗体、可溶性受体或其他拮抗剂）相比，疫苗需要更小剂量的蛋白质来诱导其作用。免疫反应一旦通过接种疫苗建立起来，就很容易通过加强疫苗来维持。骨相关疾病如类风湿性关节炎、牙周炎和骨转移的潜在病理是相似的。这种RANKL疫苗接种将是一种治疗任何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.