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.
View: Text | PDF
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

×

Figure 5

IL-6 maintains Th1 responses and IFN-γ secretion which mediates EC injury.

Options: View larger image (or click on image) Download as PowerPoint
IL-6 maintains Th1 responses and IFN-γ secretion which mediates EC injur...
(A and B) 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. (A) Expression of IFN-γ and TNF in splenic T cells on day 14 (n = 6, 8, 10, and 13 from 2 experiments), as shown by representative flow plots and MFI. (B) Plasma levels of IFN-γ and TNF on day 14 (n = 12, 9 per group from 2 experiments). (C and D) Noninfected B6D2F1 were transplanted with TCD BM (5 × 106) from C57BL6J (WT) ± T cells (2 × 106) from WT, Ifng–/–, or Tnf–/– donors (n = 6–12 from 2 experiments). On day 12, liver ECs were analyzed for (C) viability and numbers per liver and (D) expression of FcRn (MFI) relative to WT T group. (E) Noninfected B6D2F1 were transplanted with TCD BM (5 × 106) from C57BL6J (WT) mice with or without T cells (2 × 106) from WT or Ifng–/– donors, together with mouse anti–human CD4 IgG2b. Plasma levels of infused Abs were determined on day 12 (n = 4, 4, 7, 7 per group); non-BMT controls were included for comparison. (F and G) Experiments were conducted as described in C and D and analyzed for the expression of (F) VCAM-1 and (G) MHC-II on liver ECs. Data are presented as the median ± IQR and were analyzed with the Mann-Whitney U test (**P < 0.01, ***P < 0.001, and ****P < 0.0001).