PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (HCT) can cure many hematologic cancers and other life- threatening hematologic diseases but 20-50% of survivors develop chronic graft-versus-host disease (cGVHD), the leading cause of morbidity and mortality in transplant survivors. Chronic GVHD is an iatrogenic complication that can affect multiple organs, leading to clinical manifestations similar to autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, Sjogren?s syndrome, and lichen planus. Chronic GVHD requires prolonged treatment with potent immunosuppressive agents and is associated with high symptom burden and poor quality of life. The precise pathophysiology is unclear in humans. There are data supporting involvement of T and B cells, macrophages, dendritic cells, fibroblasts, endothelial cells, cytokines, chemokines and other proteins. However, information is derived from studies with few patients having heterogeneous clinical manifestations. This renewal application will address key gaps in our understanding: Can we identify biologically relevant cGVHD subgroups by studying large numbers of patients and using sophisticated analytic techniques to identify ?clusters? of similar patients? Is personalized medicine possible based on knowledge of underlying pathophysiology and the likelihood of response? To address these questions, we will use our extensive biorepository to test whether plasma proteins and peripheral blood cellular populations cluster with clinical manifestations. While these studies are ongoing, a new cohort will be enrolled to prospectively test the cluster findings and to investigate early biomarkers for treatment response. Participants will be enrolled prior to starting a new systemic initial or second-line cGVHD treatment, then followed at 1, 3 and 6 months later to assess clinical response. Successful completion of these aims will advance our understanding of the biologic underpinnings of the different forms of human cGVHD and guide therapeutic approaches, in order to decrease the morbidity and mortality of this common transplant complication.