title: Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis.
abstract: 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 CD3zeta. Five days following immunization, CD4(+) T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-gamma but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4(+) T-cell proliferation, increased T(H)1 and T(H)2 cytokine production, partially prevented CD3zeta down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4(+) T cells but not CD25(+) regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4(+) T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.
authors: Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610-0286, USA.
authors: Philip O
authors: PO
authors: Scumpia
authors: Matthew J
authors: MJ
authors: Delano
authors: Kindra M
authors: KM
authors: Kelly-Scumpia
authors: Jason S
authors: JS
authors: Weinstein
authors: James L
authors: JL
authors: Wynn
authors: Robert D
authors: RD
authors: Winfield
authors: Changqing
authors: C
authors: Xia
authors: Chun Shiang
authors: CS
authors: Chung
authors: Alfred
authors: A
authors: Ayala
authors: Mark A
authors: MA
authors: Atkinson
authors: Westley H
authors: WH
authors: Reeves
authors: Michael J
authors: MJ
authors: Clare-Salzler
authors: Lyle L
authors: LL
authors: Moldawer
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007154:Immune System Diseases / Q000188:drug therapy* / Q000209:etiology; D007110:Immunity, Active / Q000187:drug effects*; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000276:immunology*; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse
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