KFO 243: Early Immunological Determinants of Late Transplant Outcome (ELITE)
Final Report Abstract
After allogeneic cell or organ transplantation, our immune system sets in motion a response that determines long-term outcomes. Importantly, immune reactions initiated during the early period after transplantation tend to become exaggerated, self-perpetuating and difficult to reverse therapeutically later on. Our hypothesis was that therapeutic interventions meant to induce organ transplantation tolerance should be implemented near the time of transplantation. Considering this theory, KFO 243 intended to learn more about early control of immunological reactions with the end-goal to design novel therapeutic approaches to improve long-term outcomes. Results from KFO 243 fully support this hypothesis. Project 1 investigators hypothesized and confirmed that antimicrobial peptides (AMP) are critical in early GvHD development. Of particular note, they characterized an AMP called Reg3α, and testing in mice and humans shows its expression alters the gut microbiome, which affects GvHD. This research has unexpectedly led to new therapeutic approaches to treat GvHD. Investigators from Project 2 set out to clarify the role of NOD2/CARD15 and vitamin D3 on monocytes and T cell differentiation, and found that NOD2 polymorphisms do affect monocyte differentiation, but NOD2 is not involved in vitamin D3 metabolism. Nonetheless, vitamin D3 metabolizing enzymes associate with GvHD outcomes and metabolites reinforce Treg numbers that are envisioned to reduce GvHD. Project 3 and 4 investigators worked synergistically to find new mechanisms and therapeutic targets to reduce organ fibrosis after transplantation. This fruitful cooperative effort produced multiple papers, exposing new potential therapeutic targets involving IL-13/TGF-β1, TREM-1 and DNGR-1, as well as IL-4-producing basophils and collagen-depositing fibrocytes. Project 5 investigators were productive in determining the role of NK cell subsets and γδ T cells in transplant rejection, reperfusion injury and tolerance. These studies have opened the way for new targeting strategies and have layed plans for clinical trials to reduce ischemia reperfusion injury. Work in Project 6 revealed that GvHD has a profound effect on B cell reconstitution in mice that stems from inhibition of early B cell differentiation in the bone marrow. Importantly, the investigators showed that B cell recovery could be improved with Treg cell therapy, which is now being examined in human GvHD. Therefore, each project within KFO 243 has been productive in achieving our aim of learning about the early immune reactions after cell or organ transplantation. Critically, through our established network, we now have new therapeutic targets to further research and test in clinical trials to improve long-term transplant outcomes.
