T Cell- and Monocyte-Specific RNA-Sequencing Analysis in Septic and Nonseptic Critically Ill Patients and in Patients with Cancer.

Autor:	Washburn ML; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426; michael.l.washburn@gsk.com hotch@wustl.edu., Wang Z; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426.; Institute of Ecological Science, School of Life Science, South China Normal University, Guangzhou 510630, China., Walton AH; Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110., Goedegebuure SP; Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110.; Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110; and., Figueroa DJ; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Van Horn S; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Grossman J; Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110., Remlinger K; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Madsen H; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Brown J; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Srinivasan R; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Wolf AI; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Berger SB; Pharmaceuticals Research and Development, GlaxoSmithKline, Collegeville, PA 19426., Yi VN; Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110., Hawkins WG; Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110.; Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110; and., Fields RC; Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110.; Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110; and., Hotchkiss RS; Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110; michael.l.washburn@gsk.com hotch@wustl.edu.; Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110.; Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Oct 01; Vol. 203 (7), pp. 1897-1908. Date of Electronic Publication: 2019 Sep 04.
DOI:	10.4049/jimmunol.1900560
Abstrakt:	Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The purpose of this investigation was to determine the differential effect of sepsis on innate versus adaptive immunity, in humans, by examining RNA expression in specific immune cell subsets, including monocytes/macrophages and CD4 and CD8 T cells. A second aim was to determine immunosuppressive mechanisms operative in sepsis that might be amenable to immunotherapy. Finally, we examined RNA expression in peripheral cells from critically ill nonseptic patients and from cancer patients to compare the unique immune response in these disorders with that occurring in sepsis. Monocytes, CD4 T cells, and CD8 T cells from septic patients, critically ill nonseptic patients, patients with metastatic colon cancer, and healthy controls were analyzed by RNA sequencing. Sepsis induced a marked phenotypic shift toward downregulation of multiple immune response pathways in monocytes suggesting that impaired innate immunity may be fundamental to the immunosuppression that characterizes the disorder. In the sepsis cohort, there was a much more pronounced effect on gene transcription in CD4 T cells than in CD8 T cells. Potential mediators of sepsis-induced immunosuppression included Arg-1 , SOCS-1 , and SOCS-3 , which were highly upregulated in multiple cell types. Multiple negative costimulatory molecules, including TIGIT , Lag-3 , PD-1 , and CTLA-4 , were also highly upregulated in sepsis. Although cancer had much more profound effects on gene transcription in CD8 T cells, common immunosuppressive mechanisms were present in all disorders, suggesting that immunoadjuvant therapies that are effective in one disease may also be efficacious in the others. (Copyright © 2019 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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