A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients

Polk, Hiram C.; Cheadle, William G.; Livingston, David H.; Rodriguez, Jorge Luis; Starko, Karen M.; Izu, Allen; Jaffe, Howard S.; Sonnenfeld, Gerald

doi:10.1016/0002-9610(92)90099-d

Cited by 171 publications

(81 citation statements)

References 18 publications

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“…Ex vivo studies showing that GM-CSF and IFN-γ stimulated increased HLA-DR expression on monocytes from septic patients and enhanced LPSinduced TNF-α secretion prompted several clinical trials using GM-CSF or IFN-γ in sepsis therapy (36)(37)(38)(39). However, treatment of trauma patients with IFN-γ showed only minor effects on the rate of infections and did not reduce mortality significantly, despite an IFN-γ-mediated increased HLA-DR expression on monocytes in all studies (40,41). In other trials, GM-CSF did not show any benefit in terms of postoperative septic complications (42) or survival, nevertheless it led to a faster clearance of the infection (43).…”

Section: Discussionmentioning

confidence: 97%

Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis

Flohé

Agrawal

Flohé

et al. 2008

Mol Med

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The development of immunosuppression during polymicrobial sepsis is associated with the failure of dendritic cells (DC) to promote the polarization of T helper (Th) cells toward a protective Th1 type. The aim of the study was to test potential immunomodulatory approaches to restore the capacity of splenic DC to secrete interleukin (IL) 12 that represents the key cytokine in Th1 cell polarization. Murine polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Splenic DC were isolated at different time points after CLP or sham operation, and stimulated with bacterial components in the presence or absence of neutralizing anti-IL-10 antibodies, murine interferon (IFN) γ, and/or granulocyte macrophage colony-stimulating factor (GM-CSF). DC from septic mice showed an impaired capacity to release the pro-inflammatory and Th1-promoting cytokines tumor necrosis factor α, IFN-γ, and IL-12 in response to bacterial stimuli, but secreted IL-10. Endogenous IL-10 was not responsible for the impaired IL-12 secretion. Up to 6 h after CLP, the combined treatment of DC from septic mice with IFN-γ and GM-CSF increased the secretion of IL-12. Later, DC from septic mice responded to IFN-γ and GM-CSF with increased expression of the co-stimulatory molecule CD86, while IL-12 secretion was no more enhanced. In contrast, splenic macrophages from septic mice during late sepsis responded to GM-CSF with increased cytokine release. Thus, therapy of sepsis with IFN-γ/GM-CSF might be sufficient to restore the activity of macrophages, but fails to restore DC function adequate for the development of a protective Th1-like immune response.

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Section: Discussionmentioning

confidence: 97%

Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis

Flohé

Agrawal

Flohé

et al. 2008

Mol Med

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“…Use of IFN-γ has been associated with improvements in both monocyte HLA-DR expression and cytokine production capacity and was associated with lower incidence of ventilator-associated infection after severe trauma and improved clearance of invasive infections in fungal sepsis in several small studies. 35,[50][51][52][53][54] In 1 large randomized controlled trial (RCT) of 416 injured adults, IFN-γ or placebo was given for 21 days or until hospital discharge, with those in the IFN-γ group demonstrating a Table 2 Selected human studies evaluating drugs targeting innate and adaptive immune suppression in critical illness Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN-γ, interferon gamma; IL, interleukin; mHLA-DR: monocyte HLA-DR expression, MODS, multiple organ dysfunction syndrome; PD, programed death; RCT, randomized controlled trial; TNF, tumor necrosis factor.…”

Section: Innate Immune-stimulating Agentsmentioning

confidence: 99%

Critical Illness–Induced Immune Suppression: Current State of the Science

Greathouse

Hall

2016

American Journal of Critical Care

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Critical illness comprises a heterogeneous group of serious medical conditions that typically involve an initial proinflammatory process. A compensatory anti-inflammatory response may occur that, if severe and persistent, places the patient at high risk for adverse outcomes including secondary infection and death. Monitoring strategies can identify these patients through measurement of innate and adaptive immune function. Reductions in monocyte HLA-DR expression, reduced cytokine production capacity, increased inhibitory cell surface molecule expression, and lymphopenia have all been associated with this immunesuppressed state. Intriguing data suggest that critical illness-induced immune suppression may be reversible with agents such as interferon-γ, granulocyte macrophage colony-stimulating factor, interleukin 7, or anti-programmed death-1 therapy. Future approaches for characterization of patient-specific immune derangements and individualized treatment could revolutionize how we recognize and prevent complications in critically ill patients.

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“…Several prospective randomized multicenter trials using IFN-γ have been conducted in trauma patients. However, despite interesting results regarding secondary end points in some subgroups of patients (decreased severity in nosocomial infections, decreased mortality in infected patients), they remained inconclusive regarding overall mortality or infection rates (187,188). Presneill et al (189) presented preliminary GM-CSF data in 10 patients with sepsis-induced respiratory failure.…”

Section: Future Therapeutic Strategies and Conclusionmentioning

confidence: 99%

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

Monneret

Venet

Pachot

et al. 2008

Mol Med

306

323

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A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients

Cited by 171 publications

References 18 publications

Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis

Diversity of Interferon γ and Granulocyte-Macrophage Colony-Stimulating Factor in Restoring Immune Dysfunction of Dendritic Cells and Macrophages During Polymicrobial Sepsis

Critical Illness–Induced Immune Suppression: Current State of the Science

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

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