Diabetes and other autoimmune endocrine diseases
Oral
Mohsen Khosravi-Maharlooe, MD/MSc
Postdoctoral research scientist
Columbia University
Nichole Danzl, Ph.D.
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center
Chiara Borsotti, Ph.D.
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center
Sean Campbell R., MD/PhD
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center
Aleksandar Obradovic
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center
Todd Brusko, Ph.D.
Associate Professor
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida
Kortney Rogers, B.S.
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center
Robin Goland, MD
Columbia University
Sarah Pollak
Columbia University
Robert Winchester, MD
Columbia University
David G. Savage, MD
Columbia University
Megan Sykes, M.D.
Columbia Center for Translational Immunology, Department of Medicine; Department of Microbiology & Immunology; Department of Surgery, Columbia University Medical Center
To assess the influence of genetic predisposition on type 1 diabetes (T1D)-associated immune abnormalities, we developed a Personalized Immune (PI) humanized mouse model, in which immune systems of T1D or healthy control (HC) donors develop de novo following transplantation of their bone marrow hematopoietic stem cells (HSC) and a partially HLA-matched fetal thymus into NOD.SCID.IL2Rgamma-/- (NSG) mice. T1D-derived mice produced fewer total thymocytes in human thymus grafts, lower numbers of single-positive CD4+ cells and Tregs compared to HC-derived mice, suggesting abnormal thymopoiesis. Consistently, T1D-derived mice showed lower levels of human CD4+ cell reconstitution in the periphery. Deep TCRβ sequencing of thymic and peripheral T cells from a T1D compared to a concurrent HC-derived mouse showed reduced diversity of selected thymocyte subsets and peripheral T cells in the T1D-derived animal. Peripheral T cells of T1D-derived mice showed increased proportions of activated/memory cells compared to HC-derived ones, suggesting possible HSC-intrinsic differences in T cell homeostasis. Despite decreased number of Tregs in the fetal thymic graft of T1D-derived mice, peripheral Treg frequency was similar to that in HC-derived animals and Tregs from the thymic graft had normal suppressive function. Comparison of CDR3β sequences from different thymic and peripheral T cell subsets of the PI mice to a database of T1D-reactive CDR3βs revealed fewer T1D-reactive Treg sequences in the thymus and periphery of the T1D-derived mouse compared to the HC-derived one. These data suggest that the genetic factors in T1D HSCs promote fundamental abnormalities in thymopoiesis, Treg selection and peripheral T cell homeostasis.