Editors' ChoiceSepsis

Analysis of Immunoparalysis

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Science Translational Medicine  14 Nov 2012:
Vol. 4, Issue 160, pp. 160ec208
DOI: 10.1126/scitranslmed.3005304

Severe sepsis has been classically thought to be caused by the body’s overexuberant inflammatory response to severe infection—a well-intentioned attempt to attack the infection that often has deleterious consequences. However, in recent years, a controversial new hypothesis has emerged that suggests that the hyperinflammatory initial phase of sepsis is followed by subsequent immune suppression, termed “immunoparalysis,” resulting in opportunistic infections and increased morbidity and mortality. In this context, a recent study from Leentjens and colleagues used an experimental model of sepsis to investigate whether treatments designed to stimulate the immune system in this later phase may be beneficial.

In this study, healthy human subjects were given intravenous lipopolysaccharide (LPS), also known as endotoxin, on study days 1 and 7 so as to simulate the effects of severe sepsis. Next, subjects were randomized to receive either a placebo or one of two treatments designed to stimulate the immune system [interferon-γ (IFN-γ) or granulocyte-macrophage colony stimulating factor (GM-CSF)] on study days 2, 4, and 6. In the placebo group, post-LPS levels of tumor necrosis factor–α (TNF-α), a proinflammatory cytokine, were 60% lower on day 7 than day 1, which is consistent with immunoparalysis. In contrast, in the patients treated with IFN-γ, the reduction in TNF-α on day 7 was muted, although still present. The patients treated with GM-CSF had generally similar results to the patients treated with IFN-γ, but the results were not statistically significant in the GM-CSF group. Likewise, patients treated with IFN-γ had up-regulated human leukocyte antigen (HLA)–DR on the surface of monocytes compared with the control group, whereas reduction of HLA-DR on monocytes is thought to be a surrogate marker of sepsis-related immunosuppression.

Until we can accurately, rapidly, and thoroughly quantify the status of the immune response in humans who are critically ill with sepsis, it will be difficult to test whether this approach to immunomodulation may be clinically beneficial. Moreover, we still do not know what the best immunomodulatory therapeutic agents would be in this setting. However, this work by Leentjens and colleagues takes a critical step toward testing this approach in clinical trials by developing a useful patient model to study in vivo the “immunoparalysis” of later stage sepsis.

J. Leentjens et al., Reversal of immunoparalysis in humans in vivo: A double-blind, placebo-controlled, randomized pilot study. Am. J. Respir. Crit. Care Med. 186, 838–845 (2012). [PubMed]

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