Reversal of long-term sepsis-induced immunosuppression by dendritic cells

Benjamim, Cláudia F.; Lundy, Steven K.; Lukacs, Nicholas W.; Hogaboam, Cory M.; Kunkel, Steven L.

doi:10.1182/blood-2004-08-3251

Cited by 128 publications

(131 citation statements)

References 44 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…are susceptible to a normally innocuous pathogens, and that the transfer of bone-marrow derived DC (essentially composed of mDC) prevented lethal infection (31). These data suggest that postseptic immunosuppression may be due at least in part to the persistent depletion of mDC.…”

Section: Dendritic Cells In Severe Sepsismentioning

confidence: 74%

See 1 more Smart Citation

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Riccardi¹,

Porta²,

Rovati³

et al. 2010

Cytometry

View full text Add to dashboard Cite

Background: Dendritic cells (DC) play a key role in cell-mediated immunity. We aimed to analyse the number and function of peripheral blood (PB) myeloid and plasmacytoid DC (mDC/pDC) in patients with severe sepsis.Methods: Twenty-six septic patients, 20 surgical patients (abdominal aortic aneurysm) and 20 healthy controls were enrolled in this prospective study.Results: At day 1 (enrollment in the study), septic patients showed in comparison with healthy controls, decreased mDC (P < 0.001) and increased pDC (P 5 0.03), resulting in a reduction of the mDC/ pDC ratio (P < 0.001). Surgery induced a decrease in both mDCs and pDCs level, without modification of mDC/pDC ratio. Septic patients included 15 survivors and 11 nonsurvivors. At day 1 no significant difference was found in mDC between the two groups, while pDCs were significantly higher in nonsurvivors (P 5 0.03). At the outcome, mDC were selectively increased with respect to day 1 in survivors (P 5 0.001), while no significant differences were observed as far as pDC count is concerned in both groups. Sorted DC from septic patients showed in comparison with healthy controls, reduced levels of HLA DR (P < 0.001), CD11c (P < 0.001), CD83 (P 5 0.006) and of costimulatory molecule CD86 (P 5 0.003); an up-regulation of chemokine receptor CXCR4 (P 5 0.031) and increased apoptosis (P < 0.001).Conclusions: Sepsis has a profound effect on PB DC compartment. These alterations appear to be sepsisspecific. Increased apoptosis and alteration of migration and trafficking mechanism may be involved in DC compartment modification. DC alterations could contribute to sepsis-mediated immunoparalysis. V C 2010 International Clinical Cytometry Society

show abstract

Section: Dendritic Cells In Severe Sepsismentioning

confidence: 74%

“…Several studies in murine models strongly suggests that a deviated DC behavior could account for immunosuppression observed during sepsis, (26)(27)(28)(29) and that a proper DC function is required for a successful outcome to sepsis (30,31). On the other hand, available data on human are very limited (32).…”

mentioning

confidence: 99%

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Riccardi¹,

Porta²,

Rovati³

et al. 2010

Cytometry

View full text Add to dashboard Cite

show abstract

“…Forty to 50% losses of both total (CD11c high ) and lymphoid (CD8␣ ϩ ) DC populations were seen within 24 h. Similar results have been observed by others (11,12), and Hotchkiss et al (13) have reported an increased loss of DCs from the spleens of patients who had died from sepsis. Furthermore, the intrapulmonary installation of bone marrow-derived DCs prevented lethal Aspergillosis infection in septic animals (14), suggesting a functional role for DCs in opportunistic fungal infections in the lung during sepsis.…”

mentioning

confidence: 99%

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Scumpia¹,

McAuliffe²,

O’Malley³

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

CD11c+ dendritic cells (DCs) are APCs that link innate and adaptive immunity. Although DCs are lost from spleen and lymph nodes in sepsis, their role in outcome remains unclear. Transgenic mice (B6.FVB-Tg.Itgax-DTR/EGFP.57Lan/J) expressing the diphtheria toxin (DT) receptor on the CD11c promoter (DCKO mice) received 4 ng/kg DT, which resulted in depletion of 88–95% of mature myeloid and lymphoid DCs, with less depletion (75%) of plasmacytoid DCs. Pretreatment of DCKO mice with DT resulted in reduced survival in sepsis compared with saline-pretreated DCKO mice (0 vs 54%; p < 0.05) or DT-treated wild-type littermates (0 vs 54%; p < 0.05). This increased mortality was not associated with either increased bacteremia or plasma cytokine concentrations. Intravenous injection of 107 wild-type DCs improved survival in DCKO mice (42 vs 0%; p = 0.05). These data confirm that DCs are essential in the septic response and suggest that strategies to maintain DC numbers or function may improve outcome.

show abstract

“…The dysfunction of splenic DC during acute sepsis develops into a chronic dysfunction that is maintained even after resolution of the primary infection and is associated with an impaired capacity of DC to drive an effective Th1 response (15,16). Previous studies have shown that post-septic mice can be rescued from lethal secondary infections by a treatment with DC from naive mice (16)(17)(18). These findings led to the assumption that the enhanced susceptibility of post-septic mice to secondary infections is mediated by the chronic dysfunction of DC.…”

mentioning

confidence: 99%

Modulation of Dendritic Cell Differentiation in the Bone Marrow Mediates Sustained Immunosuppression after Polymicrobial Sepsis

Pastille

Didovic

Brauckmann

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Murine polymicrobial sepsis is associated with a sustained reduction of dendritic cell (DC) numbers in lymphoid organs and with a dysfunction of DC that is considered to mediate the chronic susceptibility of post-septic mice to secondary infections. We investigated whether polymicrobial sepsis triggered an altered de novo formation and/or differentiation of DC in the bone marrow. BrdU labeling experiments indicated that polymicrobial sepsis did not affect the formation of splenic DC. DC that differentiated from bone marrow (bone marrow-derived DC [BMDC]) of post-septic mice released enhanced levels of IL-10 but did not show an altered phenotype in comparison with BMDC from sham mice. Adoptive transfer experiments of BMDC into naive mice revealed that BMDC from post-septic mice impaired Th1 priming but not Th cell expansion and suppressed the innate immune defense mechanisms against Pseudomonas bacteria in the lung. Accordingly, BMDC from post-septic mice inhibited the release of IFN-γ from NK cells that are critical for the protection against Pseudomonas. Additionally, sepsis was associated with a loss of resident DC in the bone marrow. Depletion of resident DC from bone marrow of sham mice led to the differentiation of BMDC that were impaired in Th1 priming similar to BMDC from post-septic mice. Thus, in response to polymicrobial sepsis, DC precursor cells in the bone marrow developed into regulatory DC that impaired Th1 priming and NK cell activity and mediated immunosuppression. The absence of resident DC in the bone marrow after sepsis might have contributed to the modulation of DC differentiation.

show abstract

Reversal of long-term sepsis-induced immunosuppression by dendritic cells

Cited by 128 publications

References 44 publications

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Modulation of Dendritic Cell Differentiation in the Bone Marrow Mediates Sustained Immunosuppression after Polymicrobial Sepsis

Contact Info

Product

Resources

About