Translating Novel Biomarkers of Transplant Immunity and Tolerance
Allogeneic hematopoietic stem cell transplantation (HSCT) is a major therapy for malignant diseases of the blood and bone marrow and the most potent form of immune therapy against these diseases through its graft-versus-leukemia/tumor (GVL/GVT) effect. However, the efficacy of allogeneic HSCT has been impeded by frequent and severe graft-versus- host disease (GVHD) that is tightly linked to the GVL/GVT effect. Both acute and chronic forms of GVHD exist. The immunology of GVHD and GVL responses are complex and cytokines and cellular effectors are critical. My laboratory focuses on understanding the role of cytokines and cellular effectors in the biology of GVHD/GVL by discovering and investigating biomarkers in the blood and tissue of patients following allogeneic HSCT. Currently no laboratory tests exist to predict the risk of developing GVHD, responsiveness to treatment, or patient survival. The goal of our laboratory is to develop such tests integrating both proteomic and cellular biomarkers for the diagnosis and prognosis of GVHD. For proteomics, we will utilize a three-step approach: (i) discovery of proteins in an unbiased manner with a quantitative mass-spectrometry based technology; (ii) selection of the most promising candidate proteins; and (iii) validation of these candidates in a large number of allogeneic HSCT recipients using high-throughput techniques such as ELISA assays. For the study of blood cellular biomarkers, we will analyze subsets of blood cellular components that are potential GVHD biomarkers. We are interested in both acute and chronic GVHD, which has overlapping features of immunodeficiency and symptoms of naturally occurring autoimmune disorders. Indeed a prominent clinical feature of chronic GVHD is a debilitating fibrosing skin disease whose gross and histologic features resemble scleroderma (SSc) and, less commonly, morphea. Because of these potential biological similarities between chronic GVHD and autoimmune diseases, our work is also relevant.