Intranasal Interleukin‐12 is a Powerful Adjuvant for Protective Mucosal Immunity

Arulanandam, Bernard P.; O’Toole, Margot; Metzger, Dennis W.

doi:10.1086/314996

Cited by 80 publications

(67 citation statements)

References 49 publications

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“…The precise contribution of Fc␥RI and Fc␥RIII to the phagocytosis of opsonized particles has not been defined; however, it has been shown that both receptors, and in particular Fc␥RI, exhibit a higher affinity for murine IgG2a than for IgG1 or IgG2b (16). Furthermore, IgG2a has proven to be more effective in a number of in vivo clearance responses than the other antibody isotypes (17)(18)(19)(20). Thus, if Fc-mediated phagocytosis of A␤ peptide is an important mechanism for antibody-mediated plaque clearance, then IgG2a antibodies would be expected to reduce plaque burden more efficiently than the other antibody isotypes.…”

Section: Resultsmentioning

confidence: 99%

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

Bard

Barbour

Cannon

et al. 2003

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

376

310

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Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing ␤-amyloid peptide (A␤) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the A␤ peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against A␤. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different A␤ epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of A␤ were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble A␤ was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for A␤ itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.I mmunization of the transgenic PDAPP mice with ␤-amyloid peptide (A␤)-derived immunogens results in an antibody response that facilitates the clearance of plaques within the central nervous system (CNS) (1-4). Although a number of mechanisms are likely to operate in this clearance response (5, 6), our previous findings strongly indicate that antibodymediated, Fc-dependent phagocytosis by microglial cells and͞or macrophages is important to the process (7). Importantly, a T cell response was not required for amyloid plaque clearance. When peripherally administered, antibodies against A␤ entered the CNS of PDAPP transgenic mice, decorated amyloid plaques, and induced plaque clearance. Comparing different antibodies in an ex vivo assay with sections of PDAPP or Alzheimer's disease (AD) brain, there was a strong correlation between those that produced ex vivo efficacy and those that were efficacious in vivo. Fc receptors on microglial cells were found to be key for the clearance response in this assay. However, it has been reported that antibody efficacy can also be obtained in vivo by mechanisms that are independent of Fc interactions (8). Studies have indicated that an antibody directed against the midportion of A␤, which cannot recognize amyloid plaques, appears to bind to soluble A␤ and reduce plaque deposition (6). In addition, it has been reported recently that short-term...

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Section: Resultsmentioning

confidence: 99%

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

Bard

Barbour

Cannon

et al. 2003

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

376

310

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“…IL-12 administration alone had no effect on survival. Protection did not occur in vaccinated B-cell-deficient mice [22], nor in mice lacking Fc receptor expression [30].…”

Section: For Reprint Orders Please Contact Reprints@expert-reviewscommentioning

confidence: 86%

“…In experiments with influenza virus infection, it was found that all mice given only phosphate buffered saline before viral challenge succumbed to influenza, and that intranasal immunization with influenza subunit vaccine alone provided only partial protection. However, combining the vaccine with intranasal IL-12 followed 35 days later by virus challenge resulted in 100% protection [22]. IL-12 administration alone had no effect on survival.…”

Section: For Reprint Orders Please Contact Reprints@expert-reviewscommentioning

confidence: 96%

“…These include infections induced with influenza virus [22], Streptococcus pneumoniae [23][24][25], Francisella tularensis [26] and Yersinia pestis [Kumar D, Metzger DW, Unpublished Data]. We and others have repeatedly found that intranasal treatment of mice with IL-12 leads to increases in expression of both Th1-and Th2-associated antibodies in the serum [9][10][11][12][13][14] as well as in the lung [22][23][24][25][26][27]. In a typical experiment, mice are inoculated intranasally with vaccine only or vaccine plus IL-12.…”

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confidence: 99%

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IL-12 as an adjuvant for the enhancement of protective humoral immunity

Metzger¹

2009

Expert Review of Vaccines

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“…Our laboratory has recently demonstrated that IL-12 administered intransally to adult mice serves as a potent mucosal adjuvant for anti-viral vaccination (38). In addition, we have now demonstrated in preliminary studies that endogenous IL-12 expression is a crucial component of host defense against influenza virus infection.…”

Section: Figurementioning

confidence: 89%

Neonatal Administration of IL-12 Enhances the Protective Efficacy of Antiviral Vaccines

Arulanandam

Mittler

Lee

et al. 2000

The Journal of Immunology

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Neonates are highly susceptible to infectious agents and are known to display polarized expression of Th2-like cytokines and Abs. This neonatal immune bias has important implications for the development of vaccine strategies, particularly against viral infections. We now report that coadministration of IL-12 and an influenza subunit vaccine at birth enhances the protective efficacy of antiviral vaccination. Immunization and treatment with IL-12 within 24 h of birth resulted in elevated expression of IFN-γ, IL-10, and IL-15 mRNA in the spleens of newborn mice compared with animals exposed to vaccine only. In addition, these animals showed dramatic increases in IFN-γ-, IL-2-, and IL-4-secreting cells, and in IgG2a Ab levels upon adult challenge compared with mice primed with vaccine alone. Most importantly, animals vaccinated and simultaneously treated with IL-12 at birth displayed enhanced survival after lethal challenge with infectious influenza virus as adults compared with infected animals that had been primed with vaccine alone. This augmented protection required B cells and could be transferred to naive mice by immune serum. Collectively, these results provide evidence that administration of IL-12 to neonates induces a Th1-like response in newborns and elicits protective antiviral immune memory.

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Intranasal Interleukin‐12 is a Powerful Adjuvant for Protective Mucosal Immunity

Cited by 80 publications

References 49 publications

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

Epitope and isotype specificities of antibodies to β-amyloid peptide for protection against Alzheimer's disease-like neuropathology

IL-12 as an adjuvant for the enhancement of protective humoral immunity

Neonatal Administration of IL-12 Enhances the Protective Efficacy of Antiviral Vaccines

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