title: Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation.
abstract: Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.
authors: Blair T
authors: BT
authors: Stocks
authors: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN.
authors: Analise B
authors: AB
authors: Thomas
authors: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN.
authors: Sydney K
authors: SK
authors: Elizer
authors: Departartment of Pharmacology, Vanderbilt University Medical Center, Nashville, TN.
authors: Yuantee
authors: Y
authors: Zhu
authors: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN.
authors: Andrew F
authors: AF
authors: Marshall
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.
authors: Christopher S
authors: CS
authors: Wilson
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN daniel.moore@vanderbilt.edu.|Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN.
authors: Daniel J
authors: http://orcid.org/0000-0002-6889-9345
authors: DJ
authors: Moore
mesh_terms: D064591:Allografts / Q000276:immunology / Q000378:metabolism; D000818:Animals; D005260:Female; D005434:Flow Cytometry; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010006:Osteoblasts / Q000378:metabolism
chemical_list: D017493:Leukocyte Common Antigens