B cell depletion reduces T cell activation in pancreatic islets in a murine autoimmune diabetes model
| Autor: | Joanne Davies, Evy De Leenheer, Larissa Camargo da Rosa, F. Susan Wong, Li Wen, Joanne Boldison |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Endocrinology Diabetes and Metabolism T cell Regulatory B cells T-Lymphocytes B cell depletion Mice Transgenic Lymphocyte Activation T-Lymphocytes Regulatory Article 03 medical and health sciences Islets of Langerhans Mice 0302 clinical medicine Mice Inbred NOD Insulin-Secreting Cells Internal Medicine medicine Animals Humans Transgenes B cell NOD mice CD86 Inflammation B cells B-Lymphocytes Mice Inbred BALB C Chemistry Pancreatic islets Antibodies Monoclonal medicine.disease Antigens CD20 3. Good health Interleukin-10 030104 developmental biology medicine.anatomical_structure Type 1 diabetes Diabetes Mellitus Type 1 Diabetes Mellitus Type 2 Cancer research Female Insulitis CD80 030215 immunology |
| Zdroj: | Diabetologia |
| ISSN: | 0012-186X |
| Popis: | Aims/hypothesis Type 1 diabetes is a T cell-mediated autoimmune disease characterised by the destruction of beta cells in the islets of Langerhans, resulting in deficient insulin production. B cell depletion therapy has proved successful in preventing diabetes and restoring euglycaemia in animal models of diabetes, as well as in preserving beta cell function in clinical trials in the short term. We aimed to report a full characterisation of B cell kinetics post B cell depletion, with a focus on pancreatic islets. Methods Transgenic NOD mice with a human CD20 transgene expressed on B cells were injected with an anti-CD20 depleting antibody. B cells were analysed using multivariable flow cytometry. Results There was a 10 week delay in the onset of diabetes when comparing control and experimental groups, although the final difference in the diabetes incidence, following prolonged observation, was not statistically significant (p = 0.07). The co-stimulatory molecules CD80 and CD86 were reduced on stimulation of B cells during B cell depletion and repopulation. IL-10-producing regulatory B cells were not induced in repopulated B cells in the periphery, post anti-CD20 depletion. However, the early depletion of B cells had a marked effect on T cells in the local islet infiltrate. We demonstrated a lack of T cell activation, specifically with reduced CD44 expression and effector function, including IFN-γ production from both CD4+ and CD8+ T cells. These CD8+ T cells remained altered in the pancreatic islets long after B cell depletion and repopulation. Conclusions/interpretation Our findings suggest that B cell depletion can have an impact on T cell regulation, inducing a durable effect that is present long after repopulation. We suggest that this local effect of reducing autoimmune T cell activity contributes to delay in the onset of autoimmune diabetes. Electronic supplementary material The online version of this article (10.1007/s00125-018-4597-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users. |
| Databáze: | OpenAIRE |
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