Sokolovska Anna, Hem Stanley L, HogenEsch Harm
Department of Comparative Pathobiology, Purdue University, 725 Harrison Street, West Lafayette, IN 47907, USA.
Vaccine. 2007 Jun 6;25(23):4575-85. doi: 10.1016/j.vaccine.2007.03.045. Epub 2007 Apr 19.
Aluminum-containing adjuvants are widely used in licensed human and veterinary vaccines. However, the mechanism by which these adjuvants enhance the immune response and predominantly stimulate a T(H)2 humoral immune response is not well understood. In this study, the effects of aluminum hydroxide and aluminum phosphate adjuvants on antigen presentation, expression of costimulatory molecules and cytokines by mouse dendritic cells (DCs) and the ability of DCs to induce T helper cell differentiation were investigated. Dendritic cells pulsed with ovalbumin (OVA) adsorbed to aluminum-containing adjuvants activated antigen-specific T cells more effectively than DCs pulsed with OVA alone. Aluminum hydroxide adjuvant had a significantly stronger effect than aluminum phosphate adjuvant. Both aluminum-containing adjuvants significantly increased the expression of CD86 on DCs but only aluminum hydroxide adjuvant also induced moderate expression of CD80. Aluminum-containing adjuvants stimulated the release of IL-1beta and IL-18 from DCs via caspase-1 activation. DCs incubated with LPS and OVA induced T(H)1 differentiation of naïve CD4(+) T cells. In contrast, DCs incubated with aluminum/OVA activated CD4(+) T cells to secrete IL-4 and IL-5 as well as IFN-gamma. Addition of neutralizing anti-IL-1beta antibodies decreased IL-5 production and addition of anti-IL-18 antibodies decreased both IL-4 and IL-5 production. Inhibition of IL-1beta and IL-18 secretion by DCs via inhibition of caspase-1 also led to a marked decrease of IL-4 and IL-5 by CD4(+) T cells. These results indicate that aluminum-containing adjuvants activate DCs and influence their ability to direct T(H)1 and T(H)2 responses through the secretion of IL-1beta and IL-18.
含铝佐剂广泛应用于已获许可的人用和兽用疫苗中。然而，这些佐剂增强免疫反应并主要刺激T(H)2体液免疫反应的机制尚未完全明确。在本研究中，研究了氢氧化铝和磷酸铝佐剂对小鼠树突状细胞（DCs）抗原呈递、共刺激分子和细胞因子表达以及DCs诱导T辅助细胞分化能力的影响。用吸附于含铝佐剂的卵清蛋白（OVA）脉冲处理的树突状细胞比仅用OVA脉冲处理的DCs更有效地激活抗原特异性T细胞。氢氧化铝佐剂的作用明显强于磷酸铝佐剂。两种含铝佐剂均显著增加DCs上CD86的表达，但只有氢氧化铝佐剂还诱导了CD80的适度表达。含铝佐剂通过半胱天冬酶-1激活刺激DCs释放IL-1β和IL-18。用LPS和OVA孵育的DCs诱导初始CD4(+) T细胞向T(H)1分化。相反，用铝/OVA孵育的DCs激活CD4(+) T细胞分泌IL-4和IL-5以及IFN-γ。添加中和性抗IL-1β抗体可降低IL-5的产生，添加抗IL-18抗体可降低IL-4和IL-5的产生。通过抑制半胱天冬酶-1来抑制DCs分泌IL-1β和IL-18也导致CD4(+) T细胞产生的IL-4和IL-5显著减少。这些结果表明，含铝佐剂激活DCs，并通过分泌IL-1β和IL-18影响其引导T(H)1和T(H)2反应的能力。
