Pathogenic role of IL-39/IL-39R signaling in graft-versus-host disease

Abstract Graft-versus-host disease (GVHD) remains a significant source of transplant-related mortality and morbidity after allogeneic hematopoietic cell transplantation (allo-HCT). Inflammatory cytokines play an essential role in T-cell activation and differentiation to pathogenic cells, and thus promote development and progress of GVHD. Among cytokines, IL-12 family especially IL-12 and IL-23 has been shown to substantially contribute to the pathogenesis of GVHD, at least partially through promoting Th1 differentiation and Th17 maintenance, respectively. Recently, IL-39 has been proposed as a new addition to IL-12 cytokine family that consists of p19 and EBV-induced gene 3 (Ebi3). While several groups provided compelling evidence to support the presence and activity of IL-39 in preclinical murine models as well as in clinic, others failed to validate this newly proposed cytokine especially in human cells. Our preliminary study provides evidence that IL-39 exists and correlates with GVHD development not only in preclinical murine models but also in patients after allogeneic HCT. However, the functional relevance of IL-39 has not been established. The goal of this proposal is to evaluate the pathophysiologic relevance of IL-39 in GVHD development in mice and humans. Our central hypothesis is that IL-39/IL-39R signaling promotes T-cell activation and effector function, and thus promotes GVHD pathogenesis. This hypothesis will be tested by pursuing two Specific Aims: 1) To validate the role of IL-39/IL-39R signaling in GVHD and GVL activity in preclinical models; 2) To determine the functional relevance of IL-39 in humans. The research proposed in this application is considered highly innovative, because, as a newly proposed cytokine, validation of IL-39 existence and activity is urgently needed in general, and the current study is expected to be the first investigation of IL-39 in GVHD pathogenesis. The proposed research is significant biologically and clinically, because it is expected to verify the existence and biological function of IL-39 in mouse and man, and to validate IL-39 or its receptor as a potential biomarker for diagnosis or prognosis of GVHD as well as a therapeutic target in GVHD and beyond.