A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice
Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progressi...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1114802/full |
| _version_ | 1797943414095872000 |
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| author | Xiaoyun Zhu Qiongzhen Li Varghese George Catherine Spanoudis Crystal Gilkes Niraj Shrestha Bai Liu Lin Kong Lijing You Christian Echeverri Liying Li Zheng Wang Pallavi Chaturvedi Gabriela J. Muniz Jack O. Egan Peter R. Rhode Hing C. Wong |
| author_facet | Xiaoyun Zhu Qiongzhen Li Varghese George Catherine Spanoudis Crystal Gilkes Niraj Shrestha Bai Liu Lin Kong Lijing You Christian Echeverri Liying Li Zheng Wang Pallavi Chaturvedi Gabriela J. Muniz Jack O. Egan Peter R. Rhode Hing C. Wong |
| author_sort | Xiaoyun Zhu |
| collection | DOAJ |
| description | Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases. |
| first_indexed | 2024-04-10T20:22:42Z |
| format | Article |
| id | doaj.art-fd223b2bf1514f949428226dc7b75149 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T20:22:42Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-fd223b2bf1514f949428226dc7b751492023-01-25T15:40:42ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011410.3389/fimmu.2023.11148021114802A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in miceXiaoyun ZhuQiongzhen LiVarghese GeorgeCatherine SpanoudisCrystal GilkesNiraj ShresthaBai LiuLin KongLijing YouChristian EcheverriLiying LiZheng WangPallavi ChaturvediGabriela J. MunizJack O. EganPeter R. RhodeHing C. WongAtherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1114802/fullIL-2IL-2-based fusion moleculeTregsM2 macrophagesmyeloid-derived suppressor cellsinflammatory diseases |
| spellingShingle | Xiaoyun Zhu Qiongzhen Li Varghese George Catherine Spanoudis Crystal Gilkes Niraj Shrestha Bai Liu Lin Kong Lijing You Christian Echeverri Liying Li Zheng Wang Pallavi Chaturvedi Gabriela J. Muniz Jack O. Egan Peter R. Rhode Hing C. Wong A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice Frontiers in Immunology IL-2 IL-2-based fusion molecule Tregs M2 macrophages myeloid-derived suppressor cells inflammatory diseases |
| title | A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice |
| title_full | A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice |
| title_fullStr | A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice |
| title_full_unstemmed | A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice |
| title_short | A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice |
| title_sort | novel interleukin 2 based fusion molecule hcw9302 differentially promotes regulatory t cell expansion to treat atherosclerosis in mice |
| topic | IL-2 IL-2-based fusion molecule Tregs M2 macrophages myeloid-derived suppressor cells inflammatory diseases |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1114802/full |
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