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Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock

Mathias, Brittany MD; Delmas, Amber L. BS; Ozrazgat-Baslanti, Tezcan PhD; Vanzant, Erin L. MD; Szpila, Benjamin E. MD; Mohr, Alicia M. MD; Moore, Frederick A. MD; Brakenridge, Scott C. MD; Brumback, Babette A. PhD; Moldawer, Lyle L. PhD; Efron, Philip A. MD; and the Sepsis, Critical Illness Research Center Investigators

doi: 10.1097/SLA.0000000000001783
Original Articles

Objective: We hypothesized that after sepsis in humans, MDSCs will be persistently increased, functionally immunosuppressive, and associated with adverse clinical outcomes.

Background: Cancer and sepsis have surprisingly similar immunologic responses and equally dismal long term consequences. In cancer, increased myeloid-derived suppressor cells (MDSCs) induce detrimental immunosuppression, but little is known about the role of MDSCs after sepsis.

Methods: Blood was obtained from 74 patients within 12 hours of severe sepsis/septic shock (SS/SS), and at set intervals out to 28 days, and also in 18 healthy controls. MDSCs were phenotyped for cell surface receptor expression and enriched by cell sorting. Functional and genome-wide expression analyses were performed. Multiple logistic regression analysis was conducted to determine if increased MDSC appearance was associated with in-hospital and long-term outcomes.

Results: After SS/SS, CD33+CD11b+HLA-DR−/low MDSCs were dramatically increased out to 28 days (P < 0.05). When co-cultured with MDSCs from SS/SS patients, antigen-driven T-cell proliferation and TH1/TH2 cytokine production were suppressed (P < 0.05). Additionally, septic MDSCs had suppressed HLA gene expression and up-regulated ARG1 expression (P < 0.05). Finally, SS/SS patients with persistent increased percentages of blood MDSCs had increased nosocomial infections, prolonged intensive care unit stays, and poor functional status at discharge (P < 0.05).

Conclusions: After SS/SS in humans, circulating MDSCs are persistently increased, functionally immunosuppressive, and associated with adverse outcomes. This novel observation warrants further studies. As observed in cancer immunotherapy, MDSCs could be a novel component in multimodality immunotherapy targeting detrimental inflammation and immunosuppression after SS/SS to improve currently observed dismal long-term outcomes.

*Department of Surgery, University of Florida College of Medicine, Gainesville, FL

Department of Anesthesia, University of Florida College of Medicine, Gainesville, FL

Department of Biostatistics, University of Florida College of Medicine, Gainesville, FL

§The Sepsis and Critical Illness Research Center, University of Florida College of Medicine, Gainesville, FL.

Reprints: Philip A. Efron, MD, FACS, FCCM, Department of Surgery, University of Florida College of Medicine, PO Box 10019, Gainesville, FL 32610-0019. E-mail: philip.efron@surgery.ufl.edu.

Funding: This study was supported by grant R01 GM40586-27 awarded by the NIGMS. PAE was supported by P30 AG028740 from the National Institute on Aging and by the NIH NIGMS grant 1 R01 GM113945-01. AMM was supported by NIH NIGMS grant R01 GM105893-01A1. BES and BM were supported by a training grant in burn and trauma research (T32 GM-08431). Finally, PAE, TOB, AMM, FAM, SCB, BB, and LLM were all supported by P50 GM111152–01 (NIGMS).

The Sepsis and Clinical Research Center Investigators comprised of: Ricardo Ungaro, BS; Dina C. Nacionales, MD1; M. Cecilia Lopez, BS2; Jennifer Lanz, ARNP1; Ruth Davis, RN1; Juan C. Mira, MD1; David Holden, BS1; Patrick Verdugo, BS1; Mark Segal, MD3; Azra Bihorac, MD4; Christiaan Leeuwenburgh, PhD5; and Henry V. Baker, PhD2. Departments of Surgery1, Molecular Genetics and Microbiology2, Nephrology3, Anesthesia4, Aging and Geriatrics5, University of Florida College of Medicine; Gainesville, Florida.

Conflict of interest: No conflict of or competing interests have been declared.

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