Dendritic Cells Internalize Vaccine Adjuvant after Intramuscular Injection

Dupuis, Marc; Murphy, Tyler; Higgins, Deborah; Ugozzoli, Mildred; Nest, Gary Van; Ott, Gary; McDonald, Donald M.

doi:10.1006/cimm.1998.1283

Cited by 156 publications

(86 citation statements)

References 53 publications

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“…We therefore sought to directly quantitate the number of cells that entered the site of immunization and to track them to the DLNs in CCR2 Ϫ/Ϫ and CCR2 ϩ/ϩ mice. To directly visualize cells that interacted with the Ag, we immunized mice with KLH and fluorescently labeled CFA (35). Thus, any cell that phagocytosed the Ag could be detected by fluorescence analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, any cell that phagocytosed the Ag could be detected by fluorescence analysis. Using this technique, Dupuis et al (35) showed that DiI-labeled APCs trafficked to the T cell areas of the DLNs, where they could present Ags. In our studies, ϳ70% fewer fluorescently labeled cells were found at the site of immunization in the quadriceps in the CCR2 Ϫ/Ϫ mice than in the wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

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A Mechanism for the Impaired IFN-γ Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses

Peters

Dupuis²,

Charo

2000

The Journal of Immunology

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101

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We have recently shown that mice with a targeted disruption of CCR2, the receptor for monocyte chemoattractant protein-1, have markedly impaired recruitment of macrophages to sites of inflammation. An unexpected finding in the CCR2−/− mice was a dramatic decrease in the production of IFN-γ after challenge with purified protein derivative of Mycobacterium bovis. In this study, we have investigated the mechanism of this cytokine production defect. In vitro, direct activation of splenocytes with CD3/CD28 Abs failed to reveal any differences in IFN-γ production between CCR2+/+ and CCR2−/− mice. However, after immunization, the number of Ag-specific, IFN-γ-producing cells in the draining lymph nodes was decreased by 70% in the CCR2−/− mice, suggesting an in vivo trafficking defect. Direct measurement of cell trafficking with fluorescently labeled CFA revealed a marked decrease in the number of monocytes/macrophages migrating to the site of immunization and to the draining lymph nodes in the CCR2−/− mice. The data suggest that impaired trafficking of APCs in the CCR2−/− mice contributes to the defect in IFN-γ production. These data support the idea that CCR2-positive monocytes/macrophages are critical in linking the innate and adaptive immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Mechanism for the Impaired IFN-γ Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses

Peters

Dupuis²,

Charo

2000

The Journal of Immunology

Self Cite

101

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“…Similarly to alum, MF59 could promote antigen uptake by dendritic cells in vivo (15). Moreover, it has been shown that, after i.m.…”

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confidence: 98%

Molecular and cellular signatures of human vaccine adjuvants

Mosca

Tritto

Muzzi

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

443

335

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Oil-in-water emulsions are potent human adjuvants used for effective pandemic influenza vaccines; however, their mechanism of action is still unknown. By combining microarray and immunofluorescence analysis, we monitored the effects of the adjuvants MF59 oil-in-water emulsion, CpG, and alum in the mouse muscle. MF59 induced a time-dependent change in the expression of 891 genes, whereas CpG and alum regulated 387 and 312 genes, respectively. All adjuvants modulated a common set of 168 genes and promoted antigen-presenting cell recruitment. MF59 was the stronger inducer of cytokines, cytokine receptors, adhesion molecules involved in leukocyte migration, and antigen-presentation genes. In addition, MF59 triggered a more rapid influx of CD11b؉ blood cells compared with other adjuvants. The early biomarkers selected by microarray, JunB and Ptx3, were used to identify skeletal muscle as a direct target of MF59. We propose that oil-in-water emulsions are the most efficient human vaccine adjuvants, because they induce an early and strong immunocompetent environment at the injection site by targeting muscle cells.innate immunity ͉ microarray ͉ MF59 ͉ alum ͉ CpG ͉ oligonucleotide

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“…rappuoli@novartis.com. peripheral blood mononuclear cells (7,18). In addition to antigen delivery functions, MF59 induces the local up-regulation of cytokines, chemokines, and other innate immunity genes in the muscle (19), which promote the recruitment of immune cells like monocytes, DCs, and granulocytes (20).…”

mentioning

confidence: 99%

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

Seubert

Calabrό

Santini

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

160

127

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Oil-in-water emulsions have been successfully used to increase the efficacy, immunogenicity, and cross-protection of human vaccines; however, their mechanism of action is still largely unknown. Nlrp3 inflammasome has been previously associated to the activity of alum, another adjuvant broadly used in human vaccines, and MyD88 adaptor protein is required for the adjuvanticity of most Toll-like receptor agonists. We compared the contribution of Nlrp3 and MyD88 to the adjuvanticity of alum, the oil-in-water emulsion MF59, and complete Freund's adjuvant in mice using a threecomponent vaccine against serogroup B Neisseria meningitidis (rMenB). Although the basal antibody responses to the nonadjuvanted rMenB vaccine were largely dependent on Nlrp3, the highlevel antibody responses induced by alum, MF59, or complete Freund's adjuvant did not require Nlrp3. Surprisingly, we found that MF59 requires MyD88 to enhance bactericidal antibody responses to the rMenB vaccine. Because MF59 did not activate any of the Tolllike receptors in vitro, we propose that MF59 requires MyD88 for a Toll-like receptor-independent signaling pathway.

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Dendritic Cells Internalize Vaccine Adjuvant after Intramuscular Injection

Cited by 156 publications

References 53 publications

A Mechanism for the Impaired IFN-γ Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses

A Mechanism for the Impaired IFN-γ Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses

Molecular and cellular signatures of human vaccine adjuvants

Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88

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