CD40 Modulation of Abeta-Vaccine Immune Response

描述(申请人提供)：通过CD40-CD40L系统的信号中断1)减少淀粉样前体蛋白(APP)过量产生的转基因小鼠大脑中Abeta(淀粉样β多肽)的沉积，2)减缓激活的小胶质细胞从吞噬细胞到抗原提呈表型的成熟，伴随着与炎症相关的细胞因子(IL-β1和TNF-α)的产生增加，以及3)促进抗炎反应，包括增加中枢神经系统(CNS)转化生长因子-β1和IL-10的水平，从而进一步有利于小胶质细胞的吞噬。 接种Abeta多肽可减少APP过度表达转基因小鼠中Abeta的沉积，并改善与过量脑Abeta相关的记忆障碍。在部分病例中，由于中枢神经系统炎症，Abeta免疫疗法的临床试验暂停。尽管停止了进一步的疫苗接种，但这项试验的第一批报告表明，在减缓产生脑Abeta抗体的患者的痴呆症进展速度方面取得了一些成功。关于Abeta免疫治疗作用的两个主要假说是，通过Fc受体促进小胶质细胞的吞噬作用，以及通过抗Abeta抗体外周血沉增加脑/血浓度梯度，促进脑内Abeta的清除。 这项应用提出了一种假设，即作为一种共同管理的AD(阿尔茨海默病)免疫治疗策略，抗Abeta治疗和抗CD40L信号治疗的行动将是互惠的。此外，抗CD40L抗体预计将通过增加中枢神经系统中的抗炎细胞因子(即转化生长因子-β1和IL-10)以及通过减缓小胶质细胞成熟为促炎抗原提呈表型来消除抗Aβ免疫治疗的潜在不良影响。即使改进了缺乏炎症反应特性的疫苗制剂，后一种特性也可能对患者有利。在这个方案中，我们将关注1)CD40信号对小胶质细胞吞噬和抗原提呈表型的调节；2)CD40-CD40L阻断与Abeta疫苗接种在减轻AD样病理和认知功能障碍方面的协同作用；3)脑室内注射抗CD40L抗体以减轻AD样病理。

DESCRIPTION (provided by applicant): Disruption of signaling through the CD40-CD40L system 1) reduces the deposition of Abeta (amyloid-beta peptide) in the brains of APP (amyloid precursor protein) overproducing transgenic mice, 2) slows the maturation of activated microglia from a phagocytic to an antigen presenting phenotype with attendant increased production of cytokines linked to inflammation (IL-beta1 and TNF-alpha) and 3) promotes anti-inflammatory responses, including increased levels of CNS (central nervous system) TGF-beta1 and IL-10, which further benefits the microglial phagocytosis. Vaccination with the Abeta peptide reduces Abeta deposition in APP overexpressing transgenic mice and ameliorates the memory disruption associated with excess brain Abeta. Clinical trials of Abeta immunotherapy were halted because of CNS inflammation in a subset of cases. In spite of cessation of further vaccine inoculations, the first reports from this trial suggest some success in slowing the rate of dementia progression in patients generating antibodies against brain Abeta. Two major hypotheses regarding the actions of Abeta immunotherapy are the facilitation of microglial phagocytosis via Fc receptors and promotion of Abeta removal from the brain by increasing the brain/blood concentration gradient via anti-Abeta antibody peripheral sink. This application proposes to test the hypothesis that the actions of anti-Abeta therapy and anti-CD40L signaling therapy will be mutually beneficial as a co-administrated AD (Alzheimer's disease) immunotherapy strategy. In addition, the anti-CD40L antibody is predicted to abrogate the potential adverse effects of the anti-Abeta immunotherapy by increasing anti-inflammatory cytokines in the CNS (i.e. TGF-beta1 and IL-10), as well as by slowing the maturation of the microglia into the proinflammatory antigen presenting phenotype. This latter property may be beneficial for patients even with improved vaccine preparations that lack inflammation response properties. In this proposal, we will focus on 1) CD40 signaling modulation of microglial phagocytic and antigen presentation phenotypes; 2) CD40-CD40L blockage synergizes with Abeta vaccination in mitigating AD-like pathology and cognitive impairment; 3) ICV (intracerebroventrocular) administration of anti-CD40L antibody in attenuation of AD-like pathology.