Seabrook Timothy J, Jiang Liying, Thomas Katelyn, Lemere Cynthia A
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Neuroinflammation. 2006 Jun 5;3:14. doi: 10.1186/1742-2094-3-14.
Immunotherapy for Alzheimer's disease (AD) is emerging as a potential treatment. However, a clinical trial (AN1792) was halted after adverse effects occurred in a small subset of subjects, which may have been caused by a T cell-mediated immunological response. In general, aging limits the humoral immune response, therefore, immunogens and vaccination regimes are required that induce a strong antibody response with less potential for an adverse immune response.
In the current study, we immunized both wildtype and J20 APP-tg mice with a priming injection of Abeta1-40/42, followed by multiple intranasal boosts with the novel immunogen dAbeta1-15 (16 copies of Abeta1-15 on a lysine tree), Abeta1-15 peptide or Abeta1-40/42 full length peptide.
J20 APP-tg mice primed with Abeta1-40/42 subcutaneously and subsequently boosted intranasally with Abeta1-15 peptide did not generate a cellular or humoral immune response. In contrast, J20 APP-tg mice boosted intranasally with dAbeta1-15 or full length Abeta1-40/42 produced high levels of anti-Abeta antibodies. Splenocyte proliferation was minimal in mice immunized with dAbeta1-15. Wildtype littermates of the J20 APP-tg mice produced higher amounts of anti-Abeta antibodies compared to APP-tg mice but also had low T cell proliferation. The anti-Abeta antibodies were mainly composed of IgG2b and directed to an epitope within the Abeta1-7 region, regardless of the immunogen. Examination of the brain showed a significant reduction in Abeta plaque burden in the J20 APP-tg mice producing antibodies compared to controls. Biochemically, Abeta40 or Abeta42 were also reduced in brain homogenates and elevated in plasma but the changes did not reach significance.
Our results demonstrate that priming with full length Abeta40/42 followed by boosting with dAbeta1-15 but not Abeta1-15 peptide led to a robust humoral immune response with a minimal T cell response in J20 APP-tg mice. In addition, Abeta plaque burden was reduced in mice producing anti-Abeta antibodies. Interestingly, wildtype mice produced higher levels of anti-Abeta antibodies, indicating that immune tolerance may be present in J20 APP-tg mice. Together, these data suggest that dAbeta1-15 but not Abeta1-15 peptide may be useful as a boosting immunogen in an AD vaccination regime.
阿尔茨海默病（AD）的免疫疗法正在成为一种潜在的治疗方法。然而，一项临床试验（AN1792）在一小部分受试者出现不良反应后停止，这些不良反应可能是由T细胞介导的免疫反应引起的。一般来说，衰老会限制体液免疫反应，因此，需要免疫原和疫苗接种方案来诱导强烈的抗体反应，同时降低产生不良免疫反应的可能性。
在本研究中，我们用β淀粉样蛋白1-40/42进行初次注射免疫野生型和J20淀粉样前体蛋白转基因（APP-tg）小鼠，随后用新型免疫原二聚体β淀粉样蛋白1-15（赖氨酸树上有16个拷贝的β淀粉样蛋白1-15）、β淀粉样蛋白1-15肽或β淀粉样蛋白1-40/42全长肽进行多次鼻内加强免疫。
用β淀粉样蛋白1-40/42皮下初次免疫，随后用β淀粉样蛋白1-15肽鼻内加强免疫的J20 APP-tg小鼠未产生细胞免疫或体液免疫反应。相比之下，用二聚体β淀粉样蛋白1-15或全长β淀粉样蛋白1-40/42鼻内加强免疫的J20 APP-tg小鼠产生了高水平的抗β淀粉样蛋白抗体。用二聚体β淀粉样蛋白1-15免疫的小鼠脾细胞增殖最少。J20 APP-tg小鼠的野生型同窝小鼠比APP-tg小鼠产生了更多的抗β淀粉样蛋白抗体，但T细胞增殖也较低。无论免疫原如何，抗β淀粉样蛋白抗体主要由IgG2b组成，并针对β淀粉样蛋白1-7区域内的一个表位。对大脑的检查显示，与对照组相比，产生抗体的J20 APP-tg小鼠的β淀粉样蛋白斑块负担显著降低。生化分析表明，大脑匀浆中的β淀粉样蛋白40或β淀粉样蛋白42也减少，血浆中则升高，但这些变化没有达到显著水平。
我们的结果表明，先用全长β淀粉样蛋白40/42进行初次免疫，随后用二聚体β淀粉样蛋白1-15而不是β淀粉样蛋白1-15肽进行加强免疫，可在J20 APP-tg小鼠中引发强烈的体液免疫反应，同时T细胞反应最小。此外，产生抗β淀粉样蛋白抗体的小鼠的β淀粉样蛋白斑块负担降低。有趣的是，野生型小鼠产生了更高水平的抗β淀粉样蛋白抗体，这表明J20 APP-tg小鼠可能存在免疫耐受。总之，这些数据表明，二聚体β淀粉样蛋白1-15而不是β淀粉样蛋白1-15肽可能作为AD疫苗接种方案中的加强免疫原有用。
