Host Resistance in Sepsis and Trauma

MacLean, Lloyd D.; Meakins, Jonathan L.; Taguchi, Kenneth; Duignan, J. P.; Dhillon, Kiran; Gordon, Julius

doi:10.1097/00000658-197509000-00004

Cited by 241 publications

(65 citation statements)

References 31 publications

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“…This indicates that the endogenous CD4 ϩ population during sepsis does not play a major role in outcome, likely due to an already inherent dysfunction in the CD4 ϩ T cell population produced by sepsis. It is known that an increase in apoptotic death occurs in the CD4 ϩ T cell population during sepsis (34,35) and contributes to the anergy in the T cell compartment (36,37). Similar to this T cell anergy, we observed decreased effector cell function (proliferation to a mitogenic stimulus) in the CD4 ϩ CD25 Ϫ cell population isolated from spleens of septic animals compared with sham-treated animals.…”

Section: Discussionmentioning

confidence: 99%

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Scumpia¹,

Delano²,

Kelly³

et al. 2006

The Journal of Immunology

120

100

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Regulatory T cells (Tregs), including natural CD4+CD25+ Tregs and inducible IL-10 producing T regulatory type 1 (TR1) cells, maintain tolerance and inhibit autoimmunity. Recently, increased percentages of Tregs have been observed in the blood of septic patients, and ex vivo-activated Tregs were shown to prevent polymicrobial sepsis mortality. Whether endogenous Tregs contribute to sepsis outcome remains unclear. Polymicrobial sepsis, induced by cecal ligation and puncture, caused an increased number of splenic Tregs compared with sham-treated mice. Splenic CD4+CD25+ T cells from septic mice expressed higher levels of Foxp3 mRNA and were more efficient suppressors of CD4+CD25− T effector cell proliferation. Isolated CD4+ T cells from septic mice displayed increased intracellular IL-10 staining following stimulation, indicating that TR1 cells may also be elevated in sepsis. Surprisingly, Ab depletion of total CD4+ or CD4+CD25+ populations did not affect mortality. Furthermore, no difference in survival outcome was found between CD25 or IL-10 null mice and wild-type littermates, indicating that Treg or TR1-generated IL-10 are not required for survival. These results demonstrate that, although sepsis causes a relative increase in Treg number and increases their suppressive function, their presence does not contribute significantly to overall survival in this model.

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Section: Discussionmentioning

confidence: 99%

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Scumpia¹,

Delano²,

Kelly³

et al. 2006

The Journal of Immunology

120

100

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“…In a seminal study by MacLean et al, 13 it was observed that septic patients and trauma patients that progressed to sepsis displayed an inability to develop delayed-type hypersensitivity responses. We initially used a standard system whereby we could test whether an adaptive T-cell-dependent immune response can develop in septic mice by immunizing subcutaneously with the T-cell-dependent antigen NP-KLH mixed with alum and examining antigen-specific antibody production.…”

Section: Sepsis Decreases T-cell-dependent Antibody Responsesmentioning

confidence: 99%

Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis

Scumpia¹,

Delano²,

Kelly-Scumpia³

et al. 2007

Blood

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Apoptosis of CD4 ؉ T cells and T H 2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell-dependent IgM and IgG 2a antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4 ؉ T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3. Five days following immunization, CD4 ؉ T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-␥ but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4 ؉ Tcell proliferation, increased T H 1 and T H 2 cytokine production, partially prevented IntroductionDespite numerous studies showing that prevention of lymphocyte apoptosis improves survival in animal models of sepsis, 1-4 only a few studies using cytokine/anticytokine therapies have examined whether improving leukocyte function directly may improve outcome during sepsis. [5][6][7] In a previous study, we found that despite increased regulatory T-cell (Treg) activity in sepsis, depletion of Tregs, and even depletion of all CD4 ϩ T cells, did not affect mortality in sepsis. 8 However, even in the absence of Tregs, T-effector cells from septic mice did not proliferate as well as T-effector cells from sham-treated mice. These findings suggest that the endogenous CD4 ϩ population does not play a major role in outcome during sepsis, likely due to sepsis-induced dysfunction in CD4 ϩ T cells and enhanced apoptosis. In contrast, augmentation of CD4 ϩ T-cell effector responses, either by inhibition of apoptosis or by direct stimulation, may be necessary to overcome this dysfunction.Glucocorticoid-induced tumor necrosis factor (TNF) receptor family-related gene (GITR) is a member of the TNF receptor superfamily that is expressed normally at high levels on CD4 ϩ CD25 ϩ Tregs. It is expressed at low levels on resting CD4 ϩ CD25 Ϫ and CD8 ϩ CD25 Ϫ T-effector cells but increases upon activation. Initially, GITR was found to abrogate Treg-mediated suppression, 9 but it was also found to act as a costimulatory molecule on effector T cells. 10,11 We hypothesized that stimulating CD4 ϩ effector T-cell function might be an appropriate therapeutic target during sepsis. We analyzed lymphocyte function in sepsis and determined whether anti-GITR treatment could prevent the adaptive immune dysfunction and improve survival in sepsis. We found that T-celldependent IgM and IgG 2a antibody production is reduced in septic mice. Furthermore, we find that CD4 ϩ T cells isolated from septic mice exhibit decreased CD3 chain expression, proliferate poorly to antigen nonspecific and antigen-specific stimulation, and produce less IL-2 and IFN-␥ than CD4 ϩ T cells obtained from sham-treated mi...

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“…In trauma patients, inhibitory activities affecting neutrophil chemotaxis, lymphocyte reactivity, and neutrophil chemiluminescence have been identified in the sera. [39][40][41][42] The nature of the inhibitory activity in trauma patients' sera is at present unknown. It is not clear whether it is a newly synthesized product, a protein, or a substance of a different nature.…”

Section: Discussionmentioning

confidence: 99%

Postoperative serum attenuates LPS‐induced release of TNF‐α in orthopaedic surgery

Reikerås

Sun

Wang

et al. 2007

Journal Orthopaedic Research

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Studies with ex vivo stimulation of whole blood samples from injured patients have revealed a diminished production capacity for a broad range of secretory products, including inflammatory cytokines. Recent interest has focused on the release of mediators in serum that depress the cell-mediated immune response following trauma. The involvement of the lipid mediator prostaglandin E2 (PGE2) has been assumed because it is a potent endogenous immunosuppressor. In the present study, we tested the hypothesis that inhibitory substances circulating in the patient's serum after a major musculoskeletal trauma might impair leukocyte function by evaluating the effect of such serum on cytokine release in a whole blood model. Six females and three males undergoing elective total hip replacement were included in the study. Ex vivo LPS-induced TNF-a and IL-10 were measured in whole blood sampled preoperatively and added serum taken before, at the end of operation, and at postoperative days 1 and 6 with saline as negative control. LPS induced significant releases of TNF-a and IL-10 in whole blood. Addition of preoperative, postoperative, and day-1 postoperative serum did not alter the LPS-induced release of TNF-a as compared to saline. In the presence of serum from postoperative day 6, however, the expression of TNF-a was significantly reduced as compared to saline and preoperative serum (p ¼ 0.021 and 0.008, respectively). Neither of the serum samples altered the release of IL-10. PGE2 was significantly (p ¼ 0.008) increased in serum at postoperative day 6 as compared to preoperative levels. In conclusion, these data show that at day 6 after major orthopaedic surgery, the patient serum contained activity that inhibited ex vivo LPS-induced TNF-a release. The potent TNF-a inhibitory activity found at day 6 after injury correlated with increased levels of PGE2 and indicates cellmediated hyporesponsiveness to a second stimulus. ß

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Host Resistance in Sepsis and Trauma

Cited by 241 publications

References 31 publications

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis

Postoperative serum attenuates LPS‐induced release of TNF‐α in orthopaedic surgery

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