Increased T cell recruitment to the CNS after amyloid β1-42 immunization in Alzheimer's mice overproducing transforming growth factor-β1
Increased T cell recruitment to the CNS after amyloid β1-42 immunization in Alzheimer's mice overproducing transforming growth factor-β1
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DOI：
10.1523/jneurosci.2436-06.2006
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
Wyss-Coray, Tony
中科院分区：
文献类型：
--
作者：
Buckwalter, Marion S.;Coleman, Bronwen S.;Wyss-Coray, Tony
针对淀粉样β(Aβ)肽的免疫疗法是一种正在研究中的治疗阿尔茨海默病(AD)的新疗法。由于少数患者出现脑膜脑炎，一项使用 A beta(1-42) (AN1792) 作为免疫原的临床试验被停止。细胞因子 TGF-β1 是 AD 患者大脑中免疫反应的关键调节剂。我们在此表明，大脑中 TGF-β1 的局部过度表达会增加脑膜和实质 T 淋巴细胞的数量。此外，当小鼠在年轻时而非老年时使用 AN1792 进行免疫接种时，AD 小鼠模型 [淀粉样前体蛋白 (APP) 小鼠] 中的 TGF-β 1 过度表达会导致额外 T 细胞浸润的发展。值得注意的是，只有同时过量产生 Aβ（APP 小鼠）和 TGF-β1 的小鼠在免疫后 T 淋巴细胞数量才会增加。三分之一的浸润 T 细胞呈 CD4 阳性。我们没有观察到任何基因型或治疗组中 B 淋巴细胞数量的显着差异。这些结果表明，大脑中 TGF-β 1 的过量产生可以促进 T 细胞浸润，特别是在 A beta(1-42) 免疫后。同样，AD 患者大脑中 TGF-β1 或其他免疫因子的水平可能会影响对 Aβ(1-42) 免疫的反应。
Immunotherapy targeting the amyloid beta(A beta) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using A beta(1-42) (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-beta 1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-beta 1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-beta 1 overexpression in a mouse model for AD [amyloid precursor protein (APP) mice] leads to development of additional T cell infiltrates when mice were immunized at a young but not old age with AN1792. Notably, only mice overproducing both A beta(APP mice) and TGF-beta 1 experienced a rise in T lymphocyte number after immunization. One-third of infiltrating T cells were CD4 positive. We did not observe significant differences in B lymphocyte numbers in any of the genotypes or treatment groups. These results demonstrate that TGF-beta 1 overproduction in the brain can promote T cell infiltration, in particular after A beta(1-42) immunization. Likewise, levels of TGF-beta 1 or other immune factors in brains of AD patients may influence the response to A beta(1-42) immunization.