Interferon-enhanced cytokine responsiveness in early trauma-induced immune dysfunction: a prospective observational pilot study

Severe trauma induces profound alterations in innate and adaptive immunity within hours after injury, which may contribute to increased susceptibility to secondary infections and adverse outcomes. While trauma-associated immune dysfunction has been extensively described, little is known about whether this early immune state is amenable to immunomodulation during the hyperacute phase immediately following injury. Therefore, the aim of this exploratory pilot study was to characterize the hyperacute immune response following severe trauma and to investigate whether interferon-based stimulation enhances cytokine responsiveness during this early post-injury phase. In this prospective exploratory pilot study, blood samples were obtained from 20 adult severely injured patients at the trauma scene, at the emergency room (ER), and on post-injury day 1 (PID1), and compared with samples from ten healthy controls. Immune outcomes included leukocyte subset counts, monocytic HLA-DR expression, plasma concentrations of damage-associated molecular patterns (DAMPs) and cytokines, and proteomic profiling. Functional immunosuppression and the effects of immunomodulatory therapy were assessed by measuring cytokine production following in vitro stimulation of peripheral blood mononuclear cell (PBMC) with Escherichia coli -derived lipopolysaccharide (LPS) in the presence and absence of interferon (IFN)-β, IFN-γ, anti-PD-1, and anakinra. Trauma was associated with increased circulating leukocyte counts and elevated plasma concentrations of DAMPs and cytokines, already detectable at the trauma scene. Proteomic analyses revealed both immediate and sustained alterations in inflammatory protein expression, characterised by early upregulation of cytokines and chemokines, followed by a delayed immune response and suppression of immune and tissue remodelling pathways at later timepoints. In parallel, mHLA-DR expression was reduced and in vitro cytokine production was attenuated, consistent with trauma-induced immunosuppression. Co-stimulation with IFN-β and IFN-γ enhanced cytokine responsiveness in vitro, whereas anti-PD-1 had minimal effects and anakinra further reduced cytokine production. In summary, this study demonstrates that immune responses to trauma are initiated already at the trauma scene and comprise both inflammatory and immunosuppressive mechanisms. Moreover, it highlights the immunomodulatory potential of IFN-β and IFN-γ in enhancing cytokine responsiveness in early trauma-induced immune dysfunction. The study was approved by the Medical Ethics Review Committee (METC Oost-Nederland), file number 2020–7043. Not applicable.