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.
Verfasserangaben: | Salim Oulghazi, Sarah Katharina Wegner, Gabriele SpohnORCiDGND, Nina Müller, Sabine Harenkamp, Albrecht StenzingerORCiDGND, Thalia Papayannopoulou, Halvard-Björn BonigORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-574756 |
DOI: | https://doi.org/10.3390/cells9122597 |
ISSN: | 2073-4409 |
Pubmed-Id: | https://pubmed.ncbi.nlm.nih.gov/33291571 |
Titel des übergeordneten Werkes (Englisch): | Cells |
Verlag: | MDPI |
Verlagsort: | Basel |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Veröffentlichung (online): | 04.12.2020 |
Datum der Erstveröffentlichung: | 04.12.2020 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 11.01.2021 |
Freies Schlagwort / Tag: | CD49d; VLA4; autoimmune diabetes; integrin; sialitis; type-1-diabetes |
Jahrgang: | 9 |
Ausgabe / Heft: | Article 2597 |
Seitenzahl: | 16 |
HeBIS-PPN: | 475950410 |
Institute: | Medizin / Medizin |
DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Lizenz (Deutsch): | Creative Commons - Namensnennung 4.0 |