@article{a696355a4e574eee8e880f180a2041cc,
title = "IL-6–mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation",
abstract = "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.",
author = "Ping Zhang and Peter Fleming and Andoniou, {Christopher E.} and Waltner, {Olivia G.} and Bhise, {Shruti S.} and Martins, {Jose Paulo} and McEnroe, {Benjamin A.} and Valentina Voigt and Sheridan Daly and Kuns, {Rachel D.} and Ekwe, {Adaeze P.} and Henden, {Andrea S.} and Alda Saldan and Stuart Olver and Antiopi Varelias and Corey Smith and Schmidt, {Christine R.} and Ensbey, {Kathleen S.} and Legg, {Samuel R.W.} and Tomoko Sekiguchi and Minnie, {Simone A.} and Mark Gradwell and Irma Wagenaar and Clouston, {Andrew D.} and Motoko Koyama and Furlan, {Scott N.} and Kennedy, {Glen A.} and Ward, {E. Sally} and Degli-Esposti, {Mariapia A.} and Hill, {Geoffrey R.} and Tey, {Siok Keen}",
note = "Funding Information: This work was supported in part by the National Health and Medical Research Council (NHMRC) of Australia (APP1109288, to SKT and CEA); APP2004397, to MADE, CEA, and GRH; APP1119298 and 2026377, to MADE); QIMRB (RTCC 2015, to SKT); and EverGreen (to GRH). SKT is supported by a Metro North Clinician Research Fellowship. GRH and MADE are supported by NIH grant R01 AI175535. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Joana Passos and Pavel Savitskiy (University of Southampton, Southhamptom, United Kingdom) for the preparation of the FcRn reagents. Publisher Copyright: {\textcopyright} 2024, Zhang et al.",
year = "2024",
month = apr,
day = "1",
doi = "10.1172/JCI174184",
language = "English",
volume = "134",
journal = "The Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "7",
}