Details

Autor(en) / Beteiligte

• Zhang, Ping
• Fleming, Peter
• Andoniou, Christopher E
• Waltner, Olivia G
• Bhise, Shruti S
• Martins, Jose Paulo
• McEnroe, Benjamin A
• Voigt, Valentina
• Daly, Sheridan
• Kuns, Rachel D
• Ekwe, Adaeze P
• Henden, Andrea S
• Saldan, Alda
• Olver, Stuart
• Varelias, Antiopi
• Smith, Corey
• Schmidt, Christine R
• Ensbey, Kathleen S
• Legg, Samuel Rw
• Sekiguchi, Tomoko
• Minnie, Simone A
• Gradwell, Mark
• Wagenaar, Irma
• Clouston, Andrew D
• Koyama, Motoko
• Furlan, Scott N
• Kennedy, Glen A
• Ward, E Sally
• Degli-Esposti, Mariapia A
• Hill, Geoffrey R
• Tey, Siok-Keen

Titel

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

Ist Teil von

• The Journal of clinical investigation, 2024-04, Vol.134 (7), p.1-14

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.