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

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 4

EC injury impairs FcRn recycling and promotes IgG loss.

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EC injury impairs FcRn recycling and promotes IgG loss. (A and B) Noninf...
(A and B) Noninfected B6D2F1 were transplanted with BM (5 × 106) and T cells (2 × 106) from Cd4Cre– Il6rfl/fl donors (n = 10 from 2 experiments). On day 14, liver cells were analyzed for (A) the expression of FcRn (i.e., representing IgG recycling) and (B) endocytosis (i.e., representing IgG uptake); representative histograms are shown. (C) Noninfected B6D2F1 mice were transplanted with BM (5 × 106) with or without T cells (2 × 106), and the half-life of infused IgG2b was compared between the indicated groups (n = 5, 5, 8, and 8). (D) Uninfected WT or Fcrn–/– mice were transplanted with BM (10 × 106) with or without T cells (5 × 106) from BALB/c donors. The kinetics of administered IgG2b is shown (left), and the half-life was compared between the indicated groups (n = 4, 4, 8, and 7). Liver ECs were analyzed for the expression (MFI) of FcRn (right) on day 21. (E) MCMV latently infected Fcrn–/– or WT B6 mice were transplanted with BM (10 × 106) plus T cells (3 × 106) from BALB/c donors, and MCMV viremia was quantified on day 19 (n = 13–14 per group from 2 experiments). (F) Latently MCMV-infected B6D2F1 mice were transplanted with BM (5 × 106) plus T cells (2 × 106) from B6 donors and treated with a FcRn inhibitor or a control antibody. MCMV viremia was quantified on day 21 (n = 9 per group from 2 experiments). (G–J) Noninfected B6D2F1 mice were transplanted with BM (5 × 106) with or without T cells (2 × 106) from Cd4Cre Il6rfl/fl donors, and livers were analyzed on day 14 (n = 8–12 from 2 experiments). (G) Representative flow cytometric plots showing frequencies and viability of CD31+ ECs. Max, maximum. (H) Viability and number of ECs per liver. (I) FcRn expression (MFI). (J) MFI of pHrodo dextran (left) with normalized expression relative to the non-BMT group (right). (K) Noninfected B6D2F1 mice were transplanted with BM (5 × 106) with or without T cells (2 × 106) from Cd4Cre Il6rfl/fl (Cre+) or littermate control (Cre–) donors. GVHD target organs were taken for histological analysis on day 14. Shown are representative images of liver sections (left) and pathology scores in liver, skin, and ileum (right). Scale bar: 100 μm. Data are presented as the median ± IQR and were analyzed with the Mann-Whitney U test (*P < 0.05, **P < 0.01, and ***P < 0.001).