Persistent IL-2 Receptor Signaling by IL-2/CD25 Fusion Protein Controls Diabetes in NOD Mice by Multiple Mechanisms
| Autor: | Thomas R. Malek, Alicia Santos Savio, Connor J. Dwyer, Jenny Xie, Aixin Yu, Rosmely Hernandez, Mary Struthers, Liping Yu, Jen Bon Lui, Natasha C. Ward, Sunnie Hsiung |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Recombinant Fusion Proteins Endocrinology Diabetes and Metabolism medicine.medical_treatment T cell Mice Inbred Strains chemical and pharmacologic phenomena 030209 endocrinology & metabolism Immune tolerance Mice 03 medical and health sciences 0302 clinical medicine T-Lymphocyte Subsets Diabetes Mellitus Internal Medicine medicine Animals Humans IL-2 receptor Autoantibodies NOD mice Type 1 diabetes business.industry Interleukin-2 Receptor alpha Subunit Autoantibody Receptors Interleukin-2 hemic and immune systems Immunotherapy medicine.disease 030104 developmental biology Cytokine medicine.anatomical_structure Immunology Interleukin-2 Female Immunology and Transplantation business Signal Transduction |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db20-0186 |
| Popis: | Low-dose interleukin-2 (IL-2) represents a new therapeutic approach to regulate immune homeostasis to promote immune tolerance in patients with autoimmune diseases, including type 1 diabetes. We have developed a new IL-2–based biologic, an IL-2/CD25 fusion protein, with greatly improved pharmacokinetics and pharmacodynamics when compared with recombinant IL-2 to enhance this type of immunotherapy. In this study, we show that low-dose mouse IL-2/CD25 (mIL-2/CD25), but not an equivalent amount of IL-2, prevents the onset of diabetes in NOD mice and controls diabetes in hyperglycemic mice. mIL-2/CD25 acts not only to expand regulatory T cells (Tregs) but also to increase their activation and migration into lymphoid tissues and the pancreas. Lower incidence of diabetes is associated with increased serum levels of IL-10, a cytokine readily produced by activated Tregs. These effects likely act in concert to lower islet inflammation while increasing Tregs in the remaining inflamed islets. mIL-2/CD25 treatment is also associated with lower anti-insulin autoantibody levels in part by inhibition of T follicular helper cells. Thus, long-acting mIL-2/CD25 represents an improved IL-2 analog that persistently elevates Tregs to maintain a favorable Treg/effector T cell ratio that limits diabetes by expansion of activated Tregs that readily migrate into lymphoid tissues and the pancreas while inhibiting autoantibodies. |
| Databáze: | OpenAIRE |
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