CpG Oligodeoxynucleotides Enhance Neonatal Resistance to <i>Listeria</i> Infection

Ito, Shuichi; Ishii, Ken J.; Gürsel, Mayda; Shirotra, Hidekazu; Ihata, Atsushi; Klinman, Dennis M.

doi:10.4049/jimmunol.174.2.777

Cited by 55 publications

(43 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The CD8 + DC then become efficient stimulators of CD4 T cell proliferation and extremely efficient in inducing effector cells, as measured by high levels of IFN-c production. Our observation is in accordance with several studies showing that CpG-activated DC are potent inducers of immune responses against intracellular pathogens in vivo [41,42]. It is not clear why the effect of CpG is much more potent on CD8 + DC, since both CD8 + and CD8 -DC express TLR9 and up-regulate costimulatory molecules to the same extent ( [43] and data not shown).…”

Section: Discussionsupporting

confidence: 92%

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

et al. 2005

View full text Add to dashboard Cite

Freshly isolated quiescent splenic dendritic cell (DC) subtypes differ in their capacity to activate naive CD4 T cells in culture. The CD8 + DC showed a reduced capacity to stimulate T cell proliferation compared to either of the CD8 -DC subsets, regardless of antigen and DC dose. In contrast to CD8 -DC, the quiescent CD8 + DC did not induce IFN-c production from CD4 T cells. The difference between the DC subtypes appeared to be at the level of initial surface molecule interactions, but could not be attributed to differences in expression of MHC class II or B7 family molecules, or to the expression of Fas ligand on DC. However, when activated by inclusion of the Toll-like receptor 9 ligand CpG in culture, CD8 + DC became potent stimulators of both CD4 T cell proliferation and IFN-c production. In contrast, similar activation of CD8 -DC produced a more modest increase in capacity to stimulate CD4 T cell proliferation and no increase in capacity to stimulate IFN-c production. The difference between a quiescent and an activated state is therefore more extreme for CD8 + than for CD8 -DC. The especially tight regulation of the activity of CD8 + DC may be essential for the maintenance of self tolerance.

show abstract

Section: Discussionsupporting

confidence: 92%

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The failure of these interventions in large randomized trials likely reflects underappreciated differences in the functional capacity of the neonatal host response (32). To successfully modify immune function and improve infection outcomes in human neonates, as has been done in neonatal animal models (27,33,34), consideration of the unique immuno-developmental stage of the neonate must be taken into account.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Wynn

Cvijanovich²,

Allen

et al. 2011

Mol Med

126

109

View full text Add to dashboard Cite

Septic shock is a frequent and costly problem among patients in the pediatric intensive care unit (PICU) and is associated with high mortality and devastating survivor morbidity. Genome-wide expression patterns can provide molecular granularity of the host response and offer insight into why large variations in outcomes exist. We derived whole-blood genome-wide expression patterns within 24 h of PICU admission from children with septic shock. We compared the transcriptome between septic shock developmental-age groups defined as neonates (≤28 d, n = 17), infants (1 month to 1 year, n = 62), toddlers (2-5 years, n = 54) and schoolage (≥6 years, n = 47) and age-matched controls. Direct intergroup comparisons demonstrated profound changes in neonates, relative to older children. Neonates with septic shock demonstrated reduced expression of genes representing key pathways of innate and adaptive immunity. In contrast to the largely upregulated transcriptome in all other groups, neonates exhibited a predominantly downregulated transcriptome when compared with controls. Neonates and school-age subjects had the most uniquely regulated genes relative to controls. Age-specific studies of the host response are necessary to identify developmentally relevant translational opportunities that may lead to improved sepsis outcomes.

show abstract

“…9,10 Recently, TLR9 agonist therapy with CpG DNA has been evaluated in neonatal animals with experimental infection with either lethal neurotropic arenavirus 46 or Listeria monocytogenes, 47 resulting in reduced microbial burden and improved survival in both models. The TLR7/8 agonist resiquimod has not been evaluated in any sepsis model, and no TLR agonist has been previously evaluated in vivo in neonatal mice with polymicrobial sepsis.…”

Section: Discussionmentioning

confidence: 99%

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Wynn

Scumpia²,

Winfield³

et al. 2008

Blood

159

167

View full text Add to dashboard Cite

Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b ؉ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality. IntroductionSepsis causes profound defects in innate and acquired immunity. In septic adults, circulating leukocytes fail to mount an attenuated inflammatory response, monocytes have defective antigen presentation in part due to reduced MHC class II expression, and dendritic cells and lymphocytes exhibit increased apoptosis. [1][2][3][4] These deficiencies contribute to a failure to clear primary pathogens, an increased propensity to develop superinfections, and an inability to mount adaptive immune responses. Considerable progress has been made in understanding the pathogenesis of and identifying potential immunomodulatory therapies for treating sepsis in adult animals. For example, MyD88 and type I interferon signaling pathways 5,6 are important requisites for innate and inflammatory host defense responses to pathogens. 7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis. 11,13 These studies highlight the importance of both the innate and adaptive immune systems in eliminating invading pathogens in adult mammals. However, the mechanisms of protective immunity in neonates that do not possess a fully intact immune system, and who develop sepsis at increased rates, 14 are less clear.More than 1 million babies die each year worldwide within the first 4 weeks of life from sepsis. 15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where r...

show abstract

CpG Oligodeoxynucleotides Enhance Neonatal Resistance to Listeria Infection

Cited by 55 publications

References 46 publications

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

Switching from a restricted to an effective CD4 T cell response by activating CD8+ murine dendritic cells with a Toll-like receptor 9 ligand

The Influence of Developmental Age on the Early Transcriptomic Response of Children with Septic Shock

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Contact Info

Product

Resources

About