アルツハイマー病の免疫療法

Immunotherapy for Alzheimer's disease

アルツハイマー病の病態機序には，脳内アミロイドβ（Aβ）の凝集・沈着が主要な役割を果たしていると考えられている。アルツハイマー病の免疫療法であるAβワクチン療法は，Aβに対する免疫反応，主として抗Aβ抗体によりAβを除去しようとする治療法である。アジュバントとともにAβペプチドで免疫し抗体産生を誘導する能動免疫法，抗Aβ抗体の投与による受動免疫法，Aβ遺伝子発現ベクターの投与により抗体産生を誘導する遺伝子ワクチン法がある。Aβワクチン療法は動物モデルを用いた研究結果で，病理学的なアミロイド除去効果と高次神経機能の改善が報告された。能動免疫を用いた治験が実施され，髄膜脳炎の副作用のため中止となったが，病理所見では老人斑の消失など，効果が報告された。今後，細胞性免疫による副作用が少ない改良型ワクチンの開発と，その臨床応用が期待される。最近開発されたアデノ随伴ウイルスをベクターに用いた経口Aβワクチン療法は，副作用の少ない治療法として期待される。

Amyloid β protein（Aβ）deposition in the CNS is thought to play pivotal roles in pathogenesis of Alzheimer's disease（AD）. Removal of Aβ could alter the pathology of AD and improve cognitive impairments. Aβ vaccination as an immunotherapy is designed to remove Aβ in immune-mediated manners based on amyloid cascade hypothesis. We discuss active and passive immunization and then a new oral DNA vaccine. Active immunization of Aβ Alzheimer's disease model transgenic mice showed remarkable reduction of Aβ in the brain（Shenk et al., 1999）. Clinical studies using active immunization were performed in the US and Europe. Although the trial was halted because 6％of patients developed meningoencephalitis including one death. The histopathological examination of an autopsy case revealed disappearance of amyloid deposition and invasion of T lymphocytes. Furthermore, patients who developed high titer antibodies exhibited significantly milder decline of cognitive functions（Hock et al., 2003）. Side effects of active immunization were caused by mainly strong cellular response probably due to the adjuvant, which should be solved. Passive immunization resulted in reduced Aβ deposition in amyloid-bearing animals. DNA vaccination is another potential method to induce humoral immunity. Here we report a new oral vaccine using adeno-associated virus vector carrying Aβ cDNA（AAV/Aβ vaccine）as a safe and effective therapeutic strategy. Oral administration of the vaccine without adjuvant induced the expression of Aβ within the intestines. Serum antibody levels were high, while T cell immune responses to Aβ were not detected. Amyloid burden in the brain of Alzheimer's disease model transgenic mice was markedly reduced. Immunotherapy, improved, seems to be a promising therapeutic strategy for AD.