IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

Autor:	Zhang P; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Fleming P; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia., Andoniou CE; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia., Waltner OG; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Bhise SS; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Martins JP; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., McEnroe BA; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Voigt V; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia., Daly S; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia., Kuns RD; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Ekwe AP; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Henden AS; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; University of Queensland, St Lucia, Queensland, Australia.; Royal Brisbane and Women's Hospital, Herston, Queensland, Australia., Saldan A; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; University of Queensland, St Lucia, Queensland, Australia., Olver S; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Varelias A; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; University of Queensland, St Lucia, Queensland, Australia., Smith C; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia., Schmidt CR; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Ensbey KS; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Legg SR; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Sekiguchi T; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Minnie SA; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Gradwell M; Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom., Wagenaar I; Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom., Clouston AD; Envoi Pathology, Brisbane, Queensland, Australia., Koyama M; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA., Furlan SN; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Department of Pediatrics and., Kennedy GA; University of Queensland, St Lucia, Queensland, Australia.; Royal Brisbane and Women's Hospital, Herston, Queensland, Australia., Ward ES; Cancer Sciences Unit, Centre for Cancer Immunology, University of Southampton, Southampton, United Kingdom., Degli-Esposti MA; Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia., Hill GR; Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.; Division of Medical Oncology, University of Washington, Seattle, Washington, USA., Tey SK; QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.; University of Queensland, St Lucia, Queensland, Australia.; Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Apr 01; Vol. 134 (7). Date of Electronic Publication: 2024 Apr 01.
DOI:	10.1172/JCI174184
Abstrakt:	Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.
Databáze:	MEDLINE
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