Persistent IL-2 Receptor Signaling by IL-2/CD25 Fusion Protein Controls Diabetes in NOD Mice by Multiple Mechanisms
© 2020 by the American Diabetes Association..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:69 |
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| Enthalten in: |
Diabetes - 69(2020), 11 vom: 25. Nov., Seite 2400-2413 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ward, Natasha C [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.01.2021 Date Revised 02.11.2021 published: Print-Electronic figshare: 10.2337/figshare.12841220 Citation Status MEDLINE |
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| doi: |
10.2337/db20-0186 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 by the American Diabetes Association. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Autoantibodies |2 NLM | |
| 650 | 7 | |a Interleukin-2 |2 NLM | |
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| 700 | 1 | |a Lui, Jen Bon |e verfasserin |4 aut | |
| 700 | 1 | |a Hernandez, Rosmely |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Liping |e verfasserin |4 aut | |
| 700 | 1 | |a Struthers, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Santos Savio, Alicia |e verfasserin |4 aut | |
| 700 | 1 | |a Dwyer, Connor J |e verfasserin |4 aut | |
| 700 | 1 | |a Hsiung, Sunnie |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Aixin |e verfasserin |4 aut | |
| 700 | 1 | |a Malek, Thomas R |e verfasserin |4 aut | |
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