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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 Article has an altmetric score of 7

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 1

Inhibition of IL-6 signaling attenuates CMV reactivation in humans and mice.

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Inhibition of IL-6 signaling attenuates CMV reactivation in humans and m...
(A) HCMV viremia within 100 days of BMT in a prospectively enrolled observational cohort (left) and a phase I/II clinical trial investigating the addition of tocilizumab to standard GVHD prophylaxis (right). Only samples with detectable and quantifiable HCMV DNA are plotted, representing 25 of 43 and 20 of 35 at-risk patients, respectively. Dashed lines indicate the institutional threshold for preemptive antiviral therapy at 600 copies/μL. At-risk patients were those who were HCMV-seropositive and/or received a graft from an HCMV-seropositive donor. (B) Proportion of at-risk patients with clinically significant HCMV viremia in the 2 cohorts (**P < 0.01, by Fisher’s exact test). (C) Experimental schema of the murine BMT and MCMV reactivation model (created with BioRender.com). Latently MCMV-infected (D, E, G, and H) or uninfected (F) B6D2F1 mice were transplanted with BM (5 × 106) and T cells (2 × 106) from B6.Cd4Cre+ Il6rfl/fl (Cre+) mice or littermate controls (Cre–). TCD BM (5 × 106) from Cre– donors was used in the non-GVHD control groups (TCD). (D and E) Viral loads in target organs and plasma (viremia) at weeks 4–5 after BMT (spleen: n = 9–10 per group from 2 experiments; others: n = 14–15 per group from 3 experiments). (F) Plasma IL-6 levels at week 3 in MCMV-naive recipients (GVHD groups: n = 13–14 per group from 3 experiments; TCD group: n = 4 from 1 experiment) and (G) Latently MCMV-infected recipients (GVHD groups: n = 9–10 per group from 2 experiments; TCD group: n = 5 from 1 experiment). (H) Correlation between plasma IL-6 levels and MCMV viremia 5 weeks after BMT (n = 9–10 per group from 2 experiments). Dashed lines indicate the limit of detection. Data are presented as the median ± IQR and were analyzed with the Mann-Whitney U test (*P < 0.05 and **P < 0.01).

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