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Biomaterials. 2015 Aug;59:172-81. doi: 10.1016/j.biomaterials.2015.04.003. Epub 2015 May 15.

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

Author information

1
Department of Biomedical Engineering, Yale University, 55 Prospect Street, 415 Malone Engineering Center, New Haven, CT 06511, USA.
2
Transplant Research Center, Beth Israel Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
3
Keck School of Medicine, University of Southern California, 2011 Zonal Ave, Los Angeles, CA 90089, USA.
4
Department of Biomedical Engineering, Yale University, 55 Prospect Street, 415 Malone Engineering Center, New Haven, CT 06511, USA; Department of Immunobiology, Yale University, 55 Prospect Street, 415 Malone Engineering Center, New Haven, CT 06511, USA.

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.

KEYWORDS:

Autoimmunity; Drug delivery; Immunomodulation; Interleukin-2; Nanoparticles; TGF-β

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