Alum-based adjuvants facilitate vaccine-driven humoral immunity, but their mechanism of action remains poorly understood. Herein, we report that lack of type II NKT cells is associated with intact, mature B cells but dampened humoral immunity following immunization with Alum-adsorbed T-dependent antigen. Type II NKT cells facilitated production of IL-4, IL-5, IL-10, IL-13, and antibody by LN and splenocyte cultures following Alum/antigen administration in vivo and antigen restimulation in vitro. Addition of IL-4 and IL-5 to type II NKT-deficient cultures restored in vitro antibody production. Intracellular staining revealed that Alum-primed type II NKT cells coordinated IL-4 secretion by T cells. Alum did not significantly affect CD1d expression in vivo, but addition of CD1d-blocking mAb diminished cytokine production and in vitro antibody production. Type II NKT cells therefore function as part of the Alum-sensing apparatus and in a CD1d-dependent manner, facilitate T(H)2-driven humoral immunity. This may have important consequences for understanding the mechanism of action of Alum-containing vaccines.
"These studies suggest that IL-4-producing myeloid cells such as eosinophils and basophils do not participate in alum adjuvanticity or Th2 responses. Recently, it has been reported that CD1d-deficient [both type-I and -II natural killer T (NKT) cell-deficient]-mice, but not Jα18-deficient (only type-I NKT cell-deficient)-mice exhibited reduced levels of antigen-specific IgG1 . Type-II NKT cells appear to be required for alum-induced antigen-specific IgG1 responses in the regulation of IL-4-producing T cells. "
[Show abstract][Hide abstract] ABSTRACT: Particulates and crystals stimulate the immune system to induce inflammatory responses. Several nanometer- to micrometer-sized particulates, such as particle matter 2.5 (PM2.5), diesel particles, and sand dust, induce pulmonary inflammation and allergic asthma. Conversely, nanometer- to micrometer-sized crystal, sphere, and hydrogel forms of aluminum salts (referred to as "alum") have been used as vaccine adjuvants to enhance antibody responses in animals and humans. Although most of these particulates induce type-2 immune responses in vivo, the molecular and immunological mechanisms of action as a vaccine adjuvant are poorly understood. In this review, recent advances in particulate adjuvant research from the standpoint of innate immune responses are discussed.
International Reviews Of Immunology 04/2013; 32(2):209-20. DOI:10.3109/08830185.2013.773326 · 4.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aluminum hydroxide (alum) is the most widely used adjuvant in human vaccines. Nevertheless, it is virtually unknown whether alum acts on B cells. In the present study, we explored the direct effect of alum on Ig expression by murine B cells in vitro. LPS-activated mouse spleen B cells were cultured with alum, and the level of isotype-specific Ig secretion, IgG1 secreting cell numbers, and Ig germ-line transcripts (GLT) were measured using ELISA, ELISPOT, and RT-PCR, respectively. Alum consistently enhanced total IgG1 production, numbers of IgG1 secreting cells, and GLTγ1 expression. These results demonstrate that alum can directly cause IgG1 isotype switching leading to IgG1 production.
[Show abstract][Hide abstract] ABSTRACT: Vaccines containing novel adjuvant formulations are increasingly reaching advanced development and licensing stages, providing new tools to fill previously unmet clinical needs. However, many adjuvants fail during product development owing to factors such as manufacturability, stability, lack of effectiveness, unacceptable levels of tolerability or safety concerns. This Review outlines the potential benefits of adjuvants in current and future vaccines and describes the importance of formulation and mechanisms of action of adjuvants. Moreover, we emphasize safety considerations and other crucial aspects in the clinical development of effective adjuvants that will help facilitate effective next-generation vaccines against devastating infectious diseases.
Nature medicine 12/2013; 19(12):1597-608. DOI:10.1038/nm.3409 · 27.36 Impact Factor
Y P Hecker, G Cantón, J Regidor-Cerrillo, F Chianini, E Morrell, L Lischinsky, L M Ortega-Mora, E A Innes, A Odeón, C M Campero, D P Moore
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