T‐helper 1 and T‐helper 2 adjuvants induce distinct differences in the magnitude, quality and kinetics of the early inflammatory response at the site of injection

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Abstract
Vaccine adjuvants activate the innate immune system and thus influence subsequent adaptive T-cell responses. However, little is known about the initial immune mechanisms preceding the adjuvant-induced differentiation of T-helper (Th) cells. The effect of a T-helper 1 (Th1) adjuvant, dimethyldioctadecylammonium liposomes with monophosphoryl lipid-A (DDA/MPL), and a T-helper 2 adjuvant, aluminium hydroxide [Al(OH)(3)], on early, innate chemotactic signals and inflammatory cell influx at the site of injection was therefore investigated. Injection of the adjuvants into the peritoneal cavity of mice demonstrated distinct differences in the magnitude, quality and kinetics of the response. The inflammatory response to DDA/MPL was prominent, inducing high local levels of pro-inflammatory cytokines, chemokines and a pronounced inflammatory exudate consisting of neutrophils, monocytes/macrophages and activated natural killer cells. This was in contrast to the response induced by Al(OH)(3), which, although sharing some of the early chemokine signals, was more moderate and consisted almost exclusively of neutrophils and eosinophils. Notably, Al(OH)(3) specifically induced the release of a significant amount of interleukin (IL)-5, whereas DDA/MPL induced high amounts of tumour necrosis factor-alpha (TNF-alpha), IL-1alpha and IL-6. Finally, a microarray analysis confirmed that the effect of DDA/MPL was broader with more than five times as many genes being specifically up-regulated after injection of DDA/MPL compared with Al(OH)(3). Thus, the adjuvants induced qualitatively distinct local inflammatory signals early after injection.