Paracrine co-delivery of TGF-β and IL-2 using CD4-targeted nanoparticles for induction and maintenance of regulatory T cells

Abstract 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...

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Bibliographic Details
Published in:Biomaterials 2015-08, Vol.59, p.172-181
Main Authors: McHugh, Michael D, Park, Jason, Uhrich, Ross, Gao, Wenda, Horwitz, David A, Fahmy, Tarek M
Format: Article
Language:English
Subjects:
Advanced Basic Science
Animals
Autoimmune diseases
Autoimmunity
Bioavailability
CD4 Antigens - immunology
Cell Line
Cytokines
Dentistry
Drug delivery
Effectors
Female
Immunomodulation
Interleukin-2
Interleukin-2 - administration & dosage
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Nanoparticles
Nanostructure
Stability
Surgical implants
T-Lymphocytes, Regulatory - immunology
TGF-β
Transforming Growth Factor beta - administration & dosage
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Summary:Abstract 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.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2015.04.003