Metabolic and CD4+ T Cell Dysregulation in Post-Transplant Diabetes Mellitus

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DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplant (HCT) recipients represent a defined population in which up to 60% of patients will develop new-onset post-transplant diabetes mellitus (PTDM) and in whom the development of diabetes presages a high rate of subsequent morbidity and mortality. Data suggests that the propagation of insulin resistance to diabetes is characterized by increased frequencies of inflammatory Th1 cells and the depletion of immunosuppresive regulatory T cells (Tregs) in visceral adipose tissue. In a cohort of HCT recipients, we have identified subsets of circulating Tregs with a gut-homing (¿4¿7+) phenotype as a marker for visceral tissue inflammation. In this cohort, the development of PTDM was predicted by increased levels of fasting c-peptide prior to transplant and an altered Treg homing phenotype after transplant. We hypothesize that PTDM is due to the exacerbation of chronic, pre-transplant insulin resistance and adipocyte inflammation, which manifests as impaired glucose homeostasis and altered frequencies of tissue-specific T cell subsets before and after HCT. Utilizing a 2-step euglycemic-hyerinsulinemic clamp and standard oral glucose tolerance testing, we will analyze insulin resistance and glucose tolerance before and after matched related donor HCT to determine the timing and mechanisms involved with the development of new-onset PTDM (Aim 1). Next we will examine the inflammatory environment before and after transplant as a generator of PTDM by enumerating circulating gut-homing Th1 cells in the recipient and their donor (Aim 2). In Aim 3 we will characterize the phenotype of the circulating Tregs identified in the preliminary data to determine their expression of GARP and Helios, markers of bona fide activated, thymus-derived (natural) Tregs. We will also analyze the function of circulating Tregs in transplant recipients to determine whether differences exist in Treg suppression or T effector cell proliferation among patients with or without PTDM. These studies, coupled with a novel career development plan utilizing co-mentorship within the fields of immunology and endocrinology, will provide the optimal training milieu for the development of a high-impact career focused on the pathogenesis, prevention, and treatment of metabolic complications following HCT.