The Journal of clinical investigation · 2024
IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.
СтатьяПоддержка службы здравоохранения СШАПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.