Divergent roles of interleukin-12p40 and interleukin-18 in severe fibrosing chronic graft-versus-host-disease, immunity, and post-transplant outcomes

Abstract

Chronic graft-versus-host disease (cGvHD) is a major cause of late morbidity after allogeneic hematopoietic stem-cell transplantation (alloHSCT), particularly in severe fibrosing forms. Although IFNγ-related cytokines have been implicated in cGvHD, their contributions to disease progression, survival, relapse, and response to immunosuppression remain unclear. In this retrospective study, 552 alloHSCT recipients with serum samples collected at cGvHD onset (or day 180 in controls) were analyzed for IFNγ-related cytokines. Among 14 cytokines, IL-12p40 and IL-18 emerged as divergent signatures. Both were elevated in patients who later developed severe fibrosing cGvHD, but their clinical associations differed markedly. IL-12p40 correlated with reduced relapse (cause-specific HR 0.88, 95% CI 0.84–0.93; p<0.001), improved overall survival (HR 0.91, 95% CI 0.87–0.95; p<0.001), and enhanced hematopoietic reconstitution. In contrast, IL-18 was associated with increased nonrelapse mortality (cause-specific HR 1.75, 95% CI 1.47–2.09; p<0.001), systemic inflammation, and endothelial stress. Antithymocyte globulin prophylaxis was associated with sustained suppression of both cytokines and reduced severe fibrosing cGvHD incidence (5.1% vs 20.3% without ATG; p<0.001). Conversely, cumulative prednisolone exposure until day 100 selectively suppressed IL-12p40 without affecting IL-18 or fibrosing cGvHD incidence. In vitro, IL-12p40 secretion was corticosteroid-sensitive, whereas IL-18 remained largely resistant. These findings identify IL-12p40 as a marker of protective immune reconstitution and graft-versus-leukemia activity, while IL-18 defines a steroid-resistant inflammatory axis linked to endothelial injury and non-relapse mortality, supporting pathway-specific immunomodulatory strategies.