Adaptive immunity and pathogenesis of diabetes: insights provided by the α4-integrin deficient NOD mouse

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 i...

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Main Authors: Oulghazi, Salim (Author) , Wegner, Sarah K. (Author) , Spohn, Gabriele (Author) , Müller, Nina (Author) , Harenkamp, Sabine (Author) , Stenzinger, Albrecht (Author) , Papayannopoulou, Thalia (Author) , Bönig, Halvard (Author)
Format: Article (Journal)
Language:English
Published: 4 December 2020
In: Cells
Year: 2020, Volume: 9, Issue: 12, Pages: 1-16
ISSN:2073-4409
DOI:10.3390/cells9122597
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cells9122597
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2073-4409/9/12/2597
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Author Notes:Salim Oulghazi, Sarah K. Wegner, Gabriele Spohn, Nina Müller, Sabine Harenkamp, Albrecht Stenzinger, Thalia Papayannopoulou and Halvard Bonig

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520 |a 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. 
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