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

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.

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 2

IL-6 signaling does not modify protective donor T cell or B cell responses to MCMV.

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IL-6 signaling does not modify protective donor T cell or B cell respons...
(A–C) Latently infected B6D2F1 mice were transplanted with BM (5 × 106) and T cells (2 × 106) from B6.Cd4Cre+ Il6rfl/fl (Cre+) mice or littermate controls (Cre–) and analyzed 4–5 weeks after BMT. (A) Numbers of CD4+ and CD8+ T cells in spleens (n = 10–12 from 3 experiments). (B) m38 tetramer+ CD8+ T cells in spleens (n = 11–12 from 3 experiments) including representative flow cytometric plots. (C) CD19+ B cells in the blood, spleen or BM (n = 11–14 from 3 experiments; BM was from femur and tibia). (D–F) Latently infected B6D2F1 mice were transplanted with BM (5 × 106) from C57BL/6J (WT) mice or with B6.μMt BM and T cells (2 × 106) from B6.Cd4Cre+ Il6rfl/fl (Cre+) mice. TCD BM (5 × 106) was administered to non-GVHD control groups (n = 10–11 per group from 2 experiments). (D) CD19+ B cells in the peripheral blood over time or in the spleen and BM (femur and tibia for BM) at week 6 after BMT. (E) MCMV viremia at weeks 5 and 6 after BMT. (F) Representative flow cytometric plots (CD90.2–CD11b–CD19– gate) showing CD138+ plasma cells in the spleen and BM at week 6 without a discernible persistent recipient (H2Dd+) population in the BM+T settings. Number of CD19–CD138+ plasma cells in the spleen and BM (femur and tibia) at week 6. Data are presented as the median ± IQR and were analyzed with the Mann-Whitney U test (*P < 0.05 and **P < 0.01).