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 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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Author:Salim Oulghazi, Sarah Katharina Wegner, Gabriele Spohn, Nina Müller, Sabine Harenkamp, Albrecht StenzingerORCiDGND, Thalia Papayannopoulou, Halvard-Björn BonigORCiDGND
Pubmed Id:
Parent Title (English):Cells
Place of publication:Basel
Document Type:Article
Date of Publication (online):2020/12/04
Date of first Publication:2020/12/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/01/11
Tag:CD49d; VLA4; autoimmune diabetes; integrin; sialitis; type-1-diabetes
Issue:Article 2597
Page Number:16
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0