Protective immunity to Listeria monocytogenes elicited by immunization with heat-killed Listeria and IL-12. Potential mechanism of IL-12 adjuvanticity

Mark Miller, Marianne J. Skeen, H. Kirk Ziegler

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The results presented here demonstrate the striking potentiating effects of IL-12 when it is combined with listerial immunogens. Although HKLM alone does not elicit strong T-cell responses, the results presented here demonstrate that the combination of HKLM and IL-12 elicited vigorous Listeria-specific Th1-type T-cell responses when administered intraperitoneally. The intensity of these responses, as well as the cytokine profiles of the Listeria-specific peritoneal T cells and macrophages, was remarkably similar to that of Listeria-infected/immune mice. These studies also revealed that typically nonimmunogenic forms of soluble listerial antigen preparations (cLLO, SLP) and LLO peptide homologs elicited intense Listeria-specific T-cell responses when administered with IL-12. In conjunction with the generation of specific T-cell responses following injection of IL-12 in combination with either killed Listeria or soluble listerial antigen preparations, macrophages from these mice expressed upregulated quantities of class II MHC and produced increased amounts of IL-12 following restimulation in vitro. Protection studies established that the Listeria-specific T-cell responses elicited by the HKLM + IL-12 mixture conferred protective immunity of mice to a lethal dose of viable L. monocytogenes. Studies designed to investigate the regulation of IL-12 production by peritoneal macrophages revealed that activated macrophages are particularly sensitive to bacterial products. However, nonviable or replication-incompetent bacteria or bacterial products injected alone were unable to influence the ability of macrophages to produce IL-12. The ability of activated macrophages to respond to HKLM was dramatically upregulated upon addition of IFN-γ and markedly downregulated in the presence of the Th2 cytokines, IL-4 and IL-10. In light of what is known about the ability of IL-12 to induce IFN-γ production by NK cells and γδ T cells, these results suggest that the exogenous addition of IL-12 may help initiate a cytokine cascade which enables the immune system to interact productively with an antigen that is typically nonimmunogenic when administered alone. These findings demonstrate that IL-12 may prove to be a powerful and broadly useful adjuvant component of particulate and soluble antigen-based vaccines directed towards many types of intracellular pathogenic microorganisms. Studies aimed at determining the generality of these findings in other infectious disease models as well as experiments designed to further elucidate the mechanism(s) of IL-12 adjuvanticity are continuing.

Original languageEnglish (US)
Pages (from-to)207-227
Number of pages21
JournalAnnals of the New York Academy of Sciences
Volume797
DOIs
StatePublished - Jan 1 1996

Fingerprint

Listeria
Immunization
Listeria monocytogenes
Interleukin-12
Immunity
Hot Temperature
T-cells
Macrophages
T-Lymphocytes
Antigens
Cytokines
Heat
Cells
Th1 Cells
Immune system
Peritoneal Macrophages
Natural Killer Cells
Interleukin-4
Microorganisms
Interleukin-10

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

Cite this

@article{da19bd0af067445fb31a993e4a837720,
title = "Protective immunity to Listeria monocytogenes elicited by immunization with heat-killed Listeria and IL-12. Potential mechanism of IL-12 adjuvanticity",
abstract = "The results presented here demonstrate the striking potentiating effects of IL-12 when it is combined with listerial immunogens. Although HKLM alone does not elicit strong T-cell responses, the results presented here demonstrate that the combination of HKLM and IL-12 elicited vigorous Listeria-specific Th1-type T-cell responses when administered intraperitoneally. The intensity of these responses, as well as the cytokine profiles of the Listeria-specific peritoneal T cells and macrophages, was remarkably similar to that of Listeria-infected/immune mice. These studies also revealed that typically nonimmunogenic forms of soluble listerial antigen preparations (cLLO, SLP) and LLO peptide homologs elicited intense Listeria-specific T-cell responses when administered with IL-12. In conjunction with the generation of specific T-cell responses following injection of IL-12 in combination with either killed Listeria or soluble listerial antigen preparations, macrophages from these mice expressed upregulated quantities of class II MHC and produced increased amounts of IL-12 following restimulation in vitro. Protection studies established that the Listeria-specific T-cell responses elicited by the HKLM + IL-12 mixture conferred protective immunity of mice to a lethal dose of viable L. monocytogenes. Studies designed to investigate the regulation of IL-12 production by peritoneal macrophages revealed that activated macrophages are particularly sensitive to bacterial products. However, nonviable or replication-incompetent bacteria or bacterial products injected alone were unable to influence the ability of macrophages to produce IL-12. The ability of activated macrophages to respond to HKLM was dramatically upregulated upon addition of IFN-γ and markedly downregulated in the presence of the Th2 cytokines, IL-4 and IL-10. In light of what is known about the ability of IL-12 to induce IFN-γ production by NK cells and γδ T cells, these results suggest that the exogenous addition of IL-12 may help initiate a cytokine cascade which enables the immune system to interact productively with an antigen that is typically nonimmunogenic when administered alone. These findings demonstrate that IL-12 may prove to be a powerful and broadly useful adjuvant component of particulate and soluble antigen-based vaccines directed towards many types of intracellular pathogenic microorganisms. Studies aimed at determining the generality of these findings in other infectious disease models as well as experiments designed to further elucidate the mechanism(s) of IL-12 adjuvanticity are continuing.",
author = "Mark Miller and Skeen, {Marianne J.} and Ziegler, {H. Kirk}",
year = "1996",
month = "1",
day = "1",
doi = "10.1111/j.1749-6632.1996.tb52962.x",
language = "English (US)",
volume = "797",
pages = "207--227",
journal = "Annals of the New York Academy of Sciences",
issn = "0077-8923",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Protective immunity to Listeria monocytogenes elicited by immunization with heat-killed Listeria and IL-12. Potential mechanism of IL-12 adjuvanticity

AU - Miller, Mark

AU - Skeen, Marianne J.

AU - Ziegler, H. Kirk

PY - 1996/1/1

Y1 - 1996/1/1

N2 - The results presented here demonstrate the striking potentiating effects of IL-12 when it is combined with listerial immunogens. Although HKLM alone does not elicit strong T-cell responses, the results presented here demonstrate that the combination of HKLM and IL-12 elicited vigorous Listeria-specific Th1-type T-cell responses when administered intraperitoneally. The intensity of these responses, as well as the cytokine profiles of the Listeria-specific peritoneal T cells and macrophages, was remarkably similar to that of Listeria-infected/immune mice. These studies also revealed that typically nonimmunogenic forms of soluble listerial antigen preparations (cLLO, SLP) and LLO peptide homologs elicited intense Listeria-specific T-cell responses when administered with IL-12. In conjunction with the generation of specific T-cell responses following injection of IL-12 in combination with either killed Listeria or soluble listerial antigen preparations, macrophages from these mice expressed upregulated quantities of class II MHC and produced increased amounts of IL-12 following restimulation in vitro. Protection studies established that the Listeria-specific T-cell responses elicited by the HKLM + IL-12 mixture conferred protective immunity of mice to a lethal dose of viable L. monocytogenes. Studies designed to investigate the regulation of IL-12 production by peritoneal macrophages revealed that activated macrophages are particularly sensitive to bacterial products. However, nonviable or replication-incompetent bacteria or bacterial products injected alone were unable to influence the ability of macrophages to produce IL-12. The ability of activated macrophages to respond to HKLM was dramatically upregulated upon addition of IFN-γ and markedly downregulated in the presence of the Th2 cytokines, IL-4 and IL-10. In light of what is known about the ability of IL-12 to induce IFN-γ production by NK cells and γδ T cells, these results suggest that the exogenous addition of IL-12 may help initiate a cytokine cascade which enables the immune system to interact productively with an antigen that is typically nonimmunogenic when administered alone. These findings demonstrate that IL-12 may prove to be a powerful and broadly useful adjuvant component of particulate and soluble antigen-based vaccines directed towards many types of intracellular pathogenic microorganisms. Studies aimed at determining the generality of these findings in other infectious disease models as well as experiments designed to further elucidate the mechanism(s) of IL-12 adjuvanticity are continuing.

AB - The results presented here demonstrate the striking potentiating effects of IL-12 when it is combined with listerial immunogens. Although HKLM alone does not elicit strong T-cell responses, the results presented here demonstrate that the combination of HKLM and IL-12 elicited vigorous Listeria-specific Th1-type T-cell responses when administered intraperitoneally. The intensity of these responses, as well as the cytokine profiles of the Listeria-specific peritoneal T cells and macrophages, was remarkably similar to that of Listeria-infected/immune mice. These studies also revealed that typically nonimmunogenic forms of soluble listerial antigen preparations (cLLO, SLP) and LLO peptide homologs elicited intense Listeria-specific T-cell responses when administered with IL-12. In conjunction with the generation of specific T-cell responses following injection of IL-12 in combination with either killed Listeria or soluble listerial antigen preparations, macrophages from these mice expressed upregulated quantities of class II MHC and produced increased amounts of IL-12 following restimulation in vitro. Protection studies established that the Listeria-specific T-cell responses elicited by the HKLM + IL-12 mixture conferred protective immunity of mice to a lethal dose of viable L. monocytogenes. Studies designed to investigate the regulation of IL-12 production by peritoneal macrophages revealed that activated macrophages are particularly sensitive to bacterial products. However, nonviable or replication-incompetent bacteria or bacterial products injected alone were unable to influence the ability of macrophages to produce IL-12. The ability of activated macrophages to respond to HKLM was dramatically upregulated upon addition of IFN-γ and markedly downregulated in the presence of the Th2 cytokines, IL-4 and IL-10. In light of what is known about the ability of IL-12 to induce IFN-γ production by NK cells and γδ T cells, these results suggest that the exogenous addition of IL-12 may help initiate a cytokine cascade which enables the immune system to interact productively with an antigen that is typically nonimmunogenic when administered alone. These findings demonstrate that IL-12 may prove to be a powerful and broadly useful adjuvant component of particulate and soluble antigen-based vaccines directed towards many types of intracellular pathogenic microorganisms. Studies aimed at determining the generality of these findings in other infectious disease models as well as experiments designed to further elucidate the mechanism(s) of IL-12 adjuvanticity are continuing.

UR - http://www.scopus.com/inward/record.url?scp=0030450508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030450508&partnerID=8YFLogxK

U2 - 10.1111/j.1749-6632.1996.tb52962.x

DO - 10.1111/j.1749-6632.1996.tb52962.x

M3 - Article

VL - 797

SP - 207

EP - 227

JO - Annals of the New York Academy of Sciences

JF - Annals of the New York Academy of Sciences

SN - 0077-8923

ER -