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Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

Inoue S, Suzuki K, Komori Y, Morishita Y, Suzuki-Utsunomiya K, Hozumi K, Inokuchi S, Sato T - Crit Care (2014)

Bottom Line: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6.Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation.Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis.

Methods: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6-8 weeks) and aged (20-22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

Results: The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased detection of gram-negative bacteria at days 14-16 and 28-32 after sepsis (P < 0.05).

Conclusions: Persistent inflammation and T cell exhaustion may be associated with decreased survival in elderly patients and mice after sepsis.

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Increased expression of negative co-stimulatory molecules in CD4+ T cells in aged mice. The proportions of CD4+ T cells expressing PD-1 (left) and CTLA-4 (right) in the spleen, lymph nodes, and peripheral blood were compared between young and aged cecal ligation and puncture (CLP)- or sham-treated mice at 24 h post surgery; n = 6 per group, **P <0.01, *P <0.05.
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Figure 5: Increased expression of negative co-stimulatory molecules in CD4+ T cells in aged mice. The proportions of CD4+ T cells expressing PD-1 (left) and CTLA-4 (right) in the spleen, lymph nodes, and peripheral blood were compared between young and aged cecal ligation and puncture (CLP)- or sham-treated mice at 24 h post surgery; n = 6 per group, **P <0.01, *P <0.05.

Mentions: Flow cytometric analysis revealed a significant increase in the number of CD4+ T cells expressing PD-1, which is a known negative co-stimulatory molecule, in aged mice relative to young mice (5.7-fold in the spleen and 7.5-fold in the lymph nodes; P <0.01; Figure 5). The number of CD4+ T cells expressing CTLA-4, which is also a negative co-stimulatory molecule, was significantly higher in aged mice than in young mice (3.3-fold in the spleen and 4.0-fold in the lymph nodes; P <0.01). In peripheral blood, sepsis induced a significant increase of PD-1 and CTLA-4 expression in CD4+ T cells in young and aged mice. The increased number of cells expressing negative co-stimulatory molecules was likely associated with the impaired activation of T cells in aged mice. These age-related immunological changes may contribute to immunosuppression in aged sepsis.


Persistent inflammation and T cell exhaustion in severe sepsis in the elderly.

Inoue S, Suzuki K, Komori Y, Morishita Y, Suzuki-Utsunomiya K, Hozumi K, Inokuchi S, Sato T - Crit Care (2014)

Increased expression of negative co-stimulatory molecules in CD4+ T cells in aged mice. The proportions of CD4+ T cells expressing PD-1 (left) and CTLA-4 (right) in the spleen, lymph nodes, and peripheral blood were compared between young and aged cecal ligation and puncture (CLP)- or sham-treated mice at 24 h post surgery; n = 6 per group, **P <0.01, *P <0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230031&req=5

Figure 5: Increased expression of negative co-stimulatory molecules in CD4+ T cells in aged mice. The proportions of CD4+ T cells expressing PD-1 (left) and CTLA-4 (right) in the spleen, lymph nodes, and peripheral blood were compared between young and aged cecal ligation and puncture (CLP)- or sham-treated mice at 24 h post surgery; n = 6 per group, **P <0.01, *P <0.05.
Mentions: Flow cytometric analysis revealed a significant increase in the number of CD4+ T cells expressing PD-1, which is a known negative co-stimulatory molecule, in aged mice relative to young mice (5.7-fold in the spleen and 7.5-fold in the lymph nodes; P <0.01; Figure 5). The number of CD4+ T cells expressing CTLA-4, which is also a negative co-stimulatory molecule, was significantly higher in aged mice than in young mice (3.3-fold in the spleen and 4.0-fold in the lymph nodes; P <0.01). In peripheral blood, sepsis induced a significant increase of PD-1 and CTLA-4 expression in CD4+ T cells in young and aged mice. The increased number of cells expressing negative co-stimulatory molecules was likely associated with the impaired activation of T cells in aged mice. These age-related immunological changes may contribute to immunosuppression in aged sepsis.

Bottom Line: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6.Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation.Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Sepsis is known as a complex immunological response with hyperinflammation in the acute phase followed by immunosuppression. Although aging is crucial in sepsis, the impact of aging on inflammation and immunosuppression is still unclear. The purpose of this study was to investigate the relationship between inflammation and immunosuppression in aged patients and mice after sepsis.

Methods: Fifty-five patients with severe sepsis and 30 healthy donors were prospectively enrolled, and 90-day survival was compared between elderly (≥ 65 years) and adult (18-64 years) septic patients with serial measurement of serum interleukin (IL)-6. Within 24 h after diagnosis of severe sepsis, peripheral blood mononuclear cells were stimulated ex vivo to measure expression of the activation maker CD25 in T cells, IL-2 levels in the supernatant, and proliferation. In the mouse study, young (6-8 weeks) and aged (20-22 months) C57/B6 mice were subjected to cecal ligation and puncture (CLP), and survival was compared after 7 days with serial measurement of serum IL-6. Expression of the negative co-stimulatory molecules, CD25, and IL-2 in CD4+ T cells was measured.

Results: The survival rate in elderly sepsis patients and aged septic mice was significantly lower than that in adult patients and young septic mice (60% vs. 93% in septic patients, 0% vs. 63% in septic mice, P < 0.05). Serum IL-6 levels in elderly sepsis patients and aged septic mice were persistently higher than those in adult patients and young septic mice. Expression of negative co-stimulatory molecules in CD4+ T cells in the spleen, lymph nodes, and peripheral blood was significantly higher in aged mice than in young mice (P < 0.01). Ex vivo stimulation decreased CD25 expression, IL-2 production, and proliferation to a greater extent in CD4+ T cells from elderly patients and aged septic mice than in those from adult patients and young septic mice. Elderly patients demonstrated increased detection of gram-negative bacteria at days 14-16 and 28-32 after sepsis (P < 0.05).

Conclusions: Persistent inflammation and T cell exhaustion may be associated with decreased survival in elderly patients and mice after sepsis.

Show MeSH
Related in: MedlinePlus