IL-39/IL-39R Signaling Drives Acute Graft-Versus-Host Disease Pathogenesis

Project Summary:

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). While donor T cells can target leukemia cells through the graft-versus-leukemia (GVL) effect, they may also attack host tissues expressing major (MHC) and/or minor histocompatibility antigens (mHAs), leading to GVHD, which can be acute (aGVHD) or chronic (cGVHD). Steroids are the first-line treatment for acute GVHD, followed by ruxolitinib. However, no validated treatments exist for steroid- and ruxolitinib-refractory cases, posing a critical unmet need. The BMT & Cellular Therapy Program at the Medical College of Wisconsin is a premier and leader center in the Midwest, performing over 350 procedures annually and leading nationally with over 35% of procedures conducted as part of interventional clinical trials, which provides a strong foundation and support for advancing GVHD studies.

This project aims to goal is to bridge the gap in knowledge of the functional relevance of IL-39 during the development of aGVHD pathogenesis by validating the biological role of IL-39/IL-39R signaling in aGVHD pathogenesis in preclinical models and its presence and function in mice and humans. The study is highly significant both biologically and clinically, as it aims to confirm the existence and biological activities of IL-39/IL-39R signaling in aGVHD in mice and humans and establish the rationale for IL-39/IL-39R as a biomarker and therapeutic target for aGVHD.