Journal
BIOMATERIALS
Volume 59, Issue -, Pages 172-181Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2015.04.003
Keywords
Autoimmunity; Drug delivery; Immunomodulation; Nanoparticies; TGF-beta; Interleukin-2
Funding
- NIH Autoimmunity Center of Excellent Pilot Award [U19 AI056363]
- Pfizer Grant
- NATIONAL CANCER INSTITUTE [P30CA016359] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI082713, U19AI056363, R21AI101918] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P30AR053495] Funding Source: NIH RePORTER
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The cytolcine 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-beta). 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-beta 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-beta 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. (C) 2015 Published by Elsevier Ltd.
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