Enhancing the Immune Response

Although aluminum-containing adjuvants are widely used in vaccines, the mechanisms whereby they potentiate the immune response have been unclear. Various agents with adjuvant activity stimulate maturation of dendritic cells (DCs), which are critical to activating adaptive immune responses; however, in vitro studies have not found any effect of aluminum-containing adjuvants on DC maturation. Kool et al . used mice that had received fluorescently labeled T cells that recognized ovalbumin (OVA) to establish that OVA emulsified with a suspension of aluminum hydroxide and magnesium hydroxide (OVA-alum) elicited a larger and more prolonged immune response than did OVA alone. Intraperitoneal (i.p.) injection of OVA-alum stimulated the rapid recruitment to the peritoneal cavity of inflammatory monocytes as well as a later increase in myeloid and plasmacytoid DCs, neutrophils, and eosinophils. OVA-alum stimulated more OVA uptake and processing by peritoneal CD11c + DCs than did OVA. Further, it stimulated DC maturation, ability to stimulate T cell proliferation, and migration to draining lymph nodes. Indeed, OVA-alum stimulated OVA uptake by inflammatory monocytes and their stimulation of T cell proliferation, as well as their migration to draining lymph nodes, expression of CD11c, and conversion to DCs. Depletion of DCs resident in specific lymph nodes abolished stimulation of T cell proliferation in those nodes by i.p. OVA, but not OVA-alum, whereas systemic depletion of CD11c + cells during immunization abolished OVA-alum’s adjuvant activity. Unlike saline or OVA, i.p. injection of OVA-alum increased peritoneal uric acid concentration. Uricase abolished OVA-alum–dependent recruitment of inflammatory monocytes to lymph nodes (also lost in mice lacking MyD88, which has been implicated in the inflammatory response to uric acid) and its adjuvant effect. The authors thus conclude that the immunostimulatory activity of aluminum-containing adjuvants depends on activation of DCs by uric acid. M. Kool, T. Soullié, M. van Nimwegen, M. A. M. Willart, F. Muskens, S. Jung, H. C. Hoogsteden, H. Hammad, B. N. Lambrecht, Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205 , 869-882 (2008). [Abstract] [Full Text]