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IL-6–mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation
Ping Zhang, … , Geoffrey R. Hill, Siok-Keen Tey
Ping Zhang, … , Geoffrey R. Hill, Siok-Keen Tey
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e174184. https://doi.org/10.1172/JCI174184.
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Research Article

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

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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.

Authors

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

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Figure 7

IL-6R inhibition with tocilizumab maintains CMV-specific humoral immunity and protection from early HCMV reactivation.

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IL-6R inhibition with tocilizumab maintains CMV-specific humoral immunit...
Participants of a phase III clinical trial who were enrolled at Royal Brisbane and Women’s Hospital and at risk for HCMV reactivation were included for analysis (n = 85). (A and B) Cumulative incidence of HCMV viremia in all at-risk patients (n = 85) and a subset of patients who received unrelated donor graft (n = 54). Broken lines represent the placebo arm, and solid lines represent the tocilizumab arm. (B) Cumulative incidence of HCMV viremia among patients who had grade 0–1 acute GVHD (n = 55) and a subset of patient who received an unrelated donor graft (n = 31). (C–E) Plasma HCMV-specific IgG levels were determined at day 30 after BMT in at-risk patients (n = 82; 1 patient was excluded because of HCMV viremia prior to day 0, and 2 patients did not have a plasma sample stored). (C) Correlation between day 30 HCMV IgG levels and donor (D) and recipient (R) serostatus. (D) Correlation between day 30 HCMV IgG levels and HCMV viremia among HCMV-seropositive recipients. Patients were categorized according to early viremia (within the first 5 weeks after BMT), late viremia (from weeks 5–14 after BMT), and no viremia (no detectable viremia within the first 14 weeks, after which HCMV monitoring was no longer routinely performed. (E) Correlation between day 30 HCMV IgG levels and the treatment arm among HCMV-seropositive recipients and the subset receiving an unrelated donor graft (right). (F) CD19+ B cell counts in the peripheral blood 30 and 60 days after BMT in HCMV-seropositive recipients. Dashed line indicates the lower limit of normal for B cell counts at 80 × 106/mL. (G) Proportions of IgD+CD27– naive B cells, IgD–CD27+ mature B cells, and CD38hi plasmablasts within the CD19+ B cell compartment in the peripheral blood at day 60. (H) Concentration of albumin in the plasma at day 14 in all the participants from the RBWH cohort. Data are presented as the median ± IQR and were analyzed with the Mann-Whitney U test (*P < 0.05, **P < 0.01, and ****P < 0.0001).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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