Salim Oulghazi1, Sarah K Wegner1, Gabriele Spohn2, Nina Müller2, Sabine Harenkamp2, Albrecht Stenzinger3, Thalia Papayannopoulou4, Halvard Bonig1,2,4. 1. Institute for Transfusion Medicine and Immunohematology, School of Medicine, Goethe University, Sandhofstraße 1, 60528 Frankfurt, Germany. 2. Institute Frankfurt, German Red Cross Blood Service BaWüHe, Sandhofstraße 1, 60528 Frankfurt, Germany. 3. Institute for Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 672, 69120 Heidelberg, Germany. 4. Department of Medicine/Division of Hematology, University of Washington, 1959 NE Pacific St., Seattle, WA 98195, USA.
Abstract
BACKGROUND: The spontaneously diabetic "non-obese diabetic" (NOD) mouse is a faithful model of human type-1 diabetes (T1D). METHODS: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NOD mice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. RESULTS: NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabetic NOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabetic NOD.α4+ mice were identical. Co- housed diabetic NOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. CONCLUSION: α4 is a potential target for primary or secondary prevention of T1D.
BACKGROUND: The spontaneously diabetic "non-obese diabetic" (NOD) mouse is a faithful model of humantype-1 diabetes (T1D). METHODS: Given the pivotal role of α4 integrin (CD49d) in other autoimmune diseases, we generated NODmice with α4-deficient hematopoiesis (NOD.α4-/-) to study the role of α4 integrin in T1D. RESULTS:NOD.α4-/- mice developed islet-specific T-cells and antibodies, albeit quantitatively less than α4+ counterparts. Nevertheless, NOD.α4-/- mice were completely and life-long protected from diabetes and insulitis. Moreover, transplantation with isogeneic α4-/- bone marrow prevented progression to T1D of pre-diabeticNOD.α4+ mice despite significant pre-existing islet cell injury. Transfer of α4+/CD3+, but not α4+/CD4+ splenocytes from diabetic to NOD.α4-/- mice induced diabetes with short latency. Despite an only modest contribution of adoptively transferred α4+/CD3+ cells to peripheral blood, pancreas-infiltrating T-cells were exclusively graft derived, i.e., α4+. Microbiota of diabetes-resistant NOD.α4-/- and pre-diabeticNOD.α4+ mice were identical. Co- housed diabeticNOD.α4+ mice showed the characteristic diabetic dysbiosis, implying causality of diabetes for dysbiosis. Incidentally, NOD.α4-/- mice were protected from autoimmune sialitis. CONCLUSION: α4 is a potential target for primary or secondary prevention of T1D.
Authors: Lisl K M Shoda; Daniel L Young; Saroja Ramanujan; Chan C Whiting; Mark A Atkinson; Jeffrey A Bluestone; George S Eisenbarth; Diane Mathis; Aldo A Rossini; Scott E Campbell; Richard Kahn; Huub T C Kreuwel Journal: Immunity Date: 2005-08 Impact factor: 31.745
Authors: Jan W Traub; Hannah L Pellkofer; Katja Grondey; Ira Seeger; Christoph Rowold; Wolfgang Brück; Leila Husseini; Silke Häusser-Kinzel; Martin S Weber Journal: J Neuroinflammation Date: 2019-11-16 Impact factor: 8.322