Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
J Clin Invest. 2024 Apr 1;134(7):e174184. doi: 10.1172/JCI174184.
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.
同种异体骨髓移植 (BMT) 后内皮细胞功能和完整性受损，但这如何广泛影响免疫反应尚不清楚。我们使用 BMT 后 CMV 再激活的临床前模型发现，IL-6 信号诱导的抗病毒体液反应受损。T 细胞中的 IL-6 信号维持 Th1 细胞，导致持续的 IFN-γ 分泌，促进内皮细胞 (EC) 损伤、丧失负责 IgG 再循环的新生 Fc 受体 (FcRn)，以及 IgG 的快速丢失。T 细胞特异性缺失 IL-6R 导致持续存在受者衍生的、CMV 特异性 IgG，并抑制 CMV 再激活。供体 T 细胞中 IFN-γ 的缺失也消除了 EC 损伤和 FcRn 丢失。在一项 III 期临床试验中，用托珠单抗阻断 IL-6R 可促进 CMV 特异性 IgG 的持续存在，并显著减轻早期 HCMV 再激活。总之，IL-6 引发 IFN-γ 依赖性 EC 损伤和随后的 IgG 丢失，导致 CMV 再激活。因此，细胞因子抑制代表了一种预防内皮损伤的合理策略，从而在免疫治疗后保留体液免疫。
