Paracrine co-delivery of TGF-β and IL-2 using CD4-targeted nanoparticles for induction and maintenance of regulatory T cells
| Autor: | Tarek M. Fahmy, Michael D McHugh, David A. Horwitz, Ross Uhrich, Wenda Gao, Jason Park |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Interleukin 2
Regulatory T cell T cell Biophysics Bioengineering Inflammation medicine.disease_cause T-Lymphocytes Regulatory Article Autoimmunity Proinflammatory cytokine Cell Line Biomaterials Paracrine signalling Mice Transforming Growth Factor beta medicine Animals Mice Inbred BALB C biology Transforming growth factor beta Mice Inbred C57BL medicine.anatomical_structure Mechanics of Materials Immunology CD4 Antigens Ceramics and Composites biology.protein Interleukin-2 Nanoparticles Female medicine.symptom medicine.drug |
| Popis: | The cytokine milieu is critical for orchestration of lineage development towards effector T cell (Teff) or regulatory T cell (Treg) subsets implicated in the progression of cancer and autoimmune disease. Importantly, the fitness and survival of the Treg subset is dependent on the cytokines Interleukin-2 (IL-2) and transforming growth factor beta (TGF-β). The production of these cytokines is impaired in autoimmunity increasing the probability of Treg conversion to aggressive effector cells in a proinflammatory microenvironment. Therapy using soluble TGF-β and IL-2 administration is hindered by the cytokines' toxic pleiotropic effects and hence bioavailability to CD4(+) T cell targets. Thus, there is a clear need for a strategy that rectifies the cytokine milieu in autoimmunity and inflammation leading to enhanced Treg stability, frequency and number. Here we show that inert biodegradable nanoparticles (NP) loaded with TGF-β and IL-2 and targeted to CD4(+) cells can induce CD4(+) Tregs in-vitro and expand their number in-vivo. The stability of induced Tregs with cytokine-loaded NP was enhanced leading to retention of their suppressive phenotype even in the presence of proinflammatory cytokines. Our results highlight the importance of a nanocarrier-based approach for stabilizing and expanding Tregs essential for cell-immunotherapy of inflammation and autoimmune disease. |
| Databáze: | OpenAIRE |
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