title: 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 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.
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, 415 Malone Engineering Center, New Haven, CT 06511, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McHugh
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, 415 Malone Engineering Center, New Haven, CT 06511, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect Street, 415 Malone Engineering Center, New Haven, CT 06511, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Uhrich
authors.affiliation: Transplant Research Center, Beth Israel Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Wenda
authors.initials: W
authors.lastname: Gao
authors.affiliation: Keck School of Medicine, University of Southern California, 2011 Zonal Ave, Los Angeles, CA 90089, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Horwitz
authors.affiliation: 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.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D002460:Cell Line; D005260:Female; D007376:Interleukin-2 / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*
chemical_list: D015704:CD4 Antigens; D007376:Interleukin-2; D016212:Transforming Growth Factor beta
keywords: Autoimmunity; Drug delivery; Immunomodulation; Interleukin-2; Nanoparticles; TGF-β