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Equine November/December 2007 (Vol 2, No 6)

Abstract Thoughts—Everyone Loves a Classic: Even the Immune System

by David J. Hurley, PhD, James N. Moore, DVM, PhD

    Li H, Nookala S, Re F: Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J Immunol 178(8):5271-5276, 2007.

    Abstract: Aluminum hydroxide (alum) is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. This study shows that alum activates caspase-1 and induces secretion of mature interleukin (IL)-1β and IL-18. Human peripheral blood mononuclear cells or dendritic cells stimulated with pure Toll-like receptor (TLR)4 and TLR2 agonists released only traces of IL-1β or IL-18, despite the fact that the IL-1β messenger RNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus alum released large amounts of IL-1β and IL-18. Alum-induced IL-1β and IL-18 production was not due to enhancement of TLR signaling but rather reflected caspase-1 activation and, in mouse dendritic cells, occurred in a MyD88-independent fashion. Secretion of other proinflammatory cytokines, such as IL-8, was not affected by alum treatments. However, TLR-induced production of IL-10 was increased and that of interferon-g-inducible protein was decreased by alum cotreatment. Considering the immunostimulatory activities of these cytokines and the ability of IL-1β to act as an adjuvant, the results of this study suggest a mechanism for the adjuvanticity of alum.

    This abstract has been adapted with permission. Copyright ©2007, The Journal of Immunology.

    Commentary: Alum (aluminum hydroxide) is the most widely used vaccine adjuvant in all species, including horses. Most of these vaccines are formulated by adsorbing the antigens to the alum particles to (1) initiate the local events that promote the generation of antibody against the antigens and (2) prolong the release of those antigens into the tissue to sustain the signals required to "build" a strong response. How alum works as an adjuvant is not well understood and has been hotly debated for many years (see Gupta1), although there is pretty good agreement that alum acts as an irritant that activates macrophages residing in tissue. It is also commonly accepted that antigens adsorbed to the surface of alum particles are slowly released in the host's tissues, thereby resulting in the sustained presence of antigen required for effective vaccine responses.2 Based on the results of many vaccines, alum is a good adjuvant for the induction of antibodies but a weak adjuvant for the induction of cell-mediated responses.2,3

    Alum has been associated with the release of inflammatory cytokines, particularly IL-1β and IL-4,3,4 with activated eosinophils in the tissues being the primary source of the IL-4.4 The IL-4 activates monocytes that are recruited to the tissues by the irritant properties of alum, resulting in enhanced production of antibody directed against the antigens in the vaccine.

    Alum is particularly interesting because it appears to be capable of inducing many important responses, even when the antigen is not adsorbed directly onto alum particles.5 For example, mixing antigen with alum under conditions that prevent antigen from binding to the alum induces a similar level of antibody induction. Because alum particles interact with water molecules in this mixture to form a gel, the release of antigen into the tissues is limited, resulting in prolonged release of antigen at the site of injection.5

    Complement also appears to play an important role in the initiation of the immune response in the tissues by alum.3 The results of several studies indicate that alum cleaves C3 and other complement components and that these complement fragments activate macrophages in the tissues and promote the activation and differentiation of monocytes that are recruited during the vaccine response.6

    The article abstracted in this column offers some important new insights into the mechanisms by which alum exerts its effects. The article demonstrates that alum induces a strong release of IL-1β and IL-18—two cytokines that are important in the induction of a strong antibody response to vaccine antigens. The authors show that alum directly activates caspase-1—an enzyme that releases the membrane-bound form of IL-1β from cells. This means that administration of alum releases a lot of IL-1β into the tissues, where it can initiate a strong proinflammatory response. This is quite different from the response initiated by endotoxin, in which expression of messenger RNA for IL-1β increases markedly, but very little IL-1β protein is released from the cells. IL-18 is also an important signal because it promotes differentiation of monocytes that enter the tissue in response to proinflammatory signals and in setting the context for antibody production. Whereas endotoxin stimulates the production of IL-8, at least in mice, alum appears to induce very small amounts of IL-8. Alum also "locks" the host cells into an antibody production mode by blocking the induction of interferon-g-induced proteins, which are strongly associated with the development of cell-mediated responses.

    The article also helps explain some of the "side effects" of alum-adjuvanted vaccines, specifically the febrile response that often follows administration of these vaccines. The strong release of IL-1β by alum promotes the development of a fever. While tumor necrosis factor"a is the cytokine that is most strongly associated with fever, IL-1β is very capable of causing fever. IL-1β can also induce significant proinflammatory responses that lead to swelling and tenderness at the vaccination site. The direct release of IL-1β induced by alum may also explain the local reactions commonly encountered with bacterial vaccines that contain endotoxin, as activation of caspase-1 by alum may be compounded by the synthesis of IL-1β that occurs in response to cell-wall components of the bacteria.

    The good news is that unlike in the past, when we were "workin' on mysteries without any clues" (Bob Seger and The Silver Bullet Band, Night Moves, 1976), we now have some significant clues to help us. However, the full and true function of alum as an adjuvant is still a mystery.

    1. Gupta RK: Aluminum compounds as vaccine adjuvants. Adv Drug Deliv Rev 32(3):155-172, 1998.

    2. Gupta RK, Rost BE, Relyveld E, Siber GR: Adjuvant properties of aluminum and calcium compounds. Pharm Biotechnol 6:229-248, 1995.

    3. HogenEsch H: Mechanisms of stimulation of the immune response by aluminum adjuvants. Vaccine 20(suppl 3):S34-S39, 2002.

    4. Ulanova M, Tarkowski A, Hahn-Zoric M, Hanson LA: The common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4"dependent mechanism. Infect Immunol 69(2):1151-1159, 2001.

    5. Romero Méndez IZ, Shi Y, HogenEsch H, Hem SL: Potentiation of the immune response to non-adsorbed antigens by aluminum-containing adjuvants. Vaccine 25(5):825"833, 2007. Epub Sept 25, 2006.

    6. Tengvall P, Askendal A, Lundström I: Studies on protein adsorption and activation of complement on hydrated aluminium surfaces in vitro. Biomaterials 10:935-940, 1998.

    References »

    NEXT: Letters (December 2007)

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