The Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
Exp Neurol. 2013 Oct;248:451-6. doi: 10.1016/j.expneurol.2013.07.006. Epub 2013 Jul 20.
The recent studies of others and of us showing robust efficacy of anti-tangle immunotherapy, directed against phosphorylated (phos)-tau protein, may pave the way to clinical trials of phos-tau immunotherapy in Alzheimer's-disease and other tauopathies. At this stage addressing the safety of the phos-tau-immunotherapy is highly needed, particularly since we have previously shown the neurotoxic potential of tau-immunotherapy, specifically of full-length unphosphorylated-tau vaccine under a CNS-proinflammatory milieu [induced by emulsification in complete-Freund's-adjuvant (CFA) and pertussis-toxin (PT)] in young wild-type (WT)-mice. The aim of our current study was to address safety aspects of the phos-tau-immunotherapy in both neurofibrillary-tangle (NFT)-mice as well as in WT-mice, under challenging conditions of repeated immunizations with phos-tau peptides under a CNS-proinflammatory milieu. NFT- and WT-mice were repeatedly immunized (7 injections in adult-, 4 in aged-mice) with phos-tau peptides emulsified in CFA-PT. A paralytic disease was evident in the phos-tau-immunized adult NFT-mice, developing progressively to 26.7% with the number of injections. Interestingly, the WT-mice were even more prone to develop neuroinflammation following phos-tau immunization, affecting 75% of the immunized mice. Aged mice were less prone to neuroinflammatory manifestations. Anti-phos-tau antibodies, detected in the serum of immunized mice, partially correlated with the neuroinflammation in WT-mice. This points that repeated phos-tau immunizations in the frame of a proinflammatory milieu may be encephalitogenic to tangle-mice, and more robustly to WT-mice, indicating that - under certain conditions - the safety of phos-tau immunotherapy is questionable.
最近其他人的研究和我们的研究都表明，针对磷酸化（phos）tau 蛋白的抗缠结免疫疗法具有强大的疗效，这可能为阿尔茨海默病和其他 tau 病的 phos-tau 免疫疗法临床试验铺平道路。在现阶段，迫切需要解决 phos-tau 免疫疗法的安全性问题，特别是因为我们之前已经表明 tau 免疫疗法具有神经毒性潜力，特别是在中枢神经系统促炎环境下（通过在完全弗氏佐剂（CFA）和百日咳毒素（PT）中乳化引起）下全长未磷酸化 tau 疫苗在年轻野生型（WT）-小鼠中。我们当前研究的目的是在神经原纤维缠结（NFT）-小鼠和 WT-小鼠中，在中枢神经系统促炎环境下重复用 phos-tau 肽免疫的挑战性条件下，解决 phos-tau 免疫疗法的安全性问题。NFT-和 WT-小鼠被反复用 CFA-PT 乳化的 phos-tau 肽免疫（成年期 7 次注射，老年期 4 次注射）。在 phos-tau 免疫成年 NFT-小鼠中，明显出现麻痹性疾病，随着注射次数的增加，进展到 26.7%。有趣的是，WT-小鼠在接受 phos-tau 免疫后甚至更容易发生神经炎症，影响了 75%的免疫小鼠。老年小鼠较少出现神经炎症表现。在免疫小鼠的血清中检测到的抗 phos-tau 抗体，与 WT 小鼠中的神经炎症部分相关。这表明在促炎环境下重复进行 phos-tau 免疫可能对缠结小鼠具有脑炎原性，对 WT 小鼠更具侵袭性，表明在某些条件下，phos-tau 免疫疗法的安全性值得怀疑。
