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

• DOI: 10.1172/jci174184
• Publication Date: 2024-03-31T18:00:32Z
• Authors: Ping Zhang; Peter Fleming; Christopher E. An...; 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...; Geoffrey R. Hill; Siok-Keen Tey
• Keywords: Interleukin-6; Immunoglobulin G; Cytomegalovirus Infections; Infant, Newborn; 610; Humans; Antiviral Agents; Research Article; Bone Marrow Transplantation; Immunity, Humoral

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.