title: Controlled release formulations of IL-2, TGF-β1 and rapamycin for the induction of regulatory T cells.
abstract: The absence of regulatory T cells (Treg) is a hallmark for a wide variety of disorders such as autoimmunity, dermatitis, periodontitis and even transplant rejection. A potential treatment option for these disorders is to increase local Treg numbers. Enhancing local numbers of Treg through in situ Treg expansion or induction could be a potential treatment option for these disorders. Current methods for in vivo Treg expansion rely on biologic therapies, which are not Treg-specific and are associated with many adverse side-effects. Synthetic formulations capable of inducing Treg could be an alternative strategy to achieve in situ increase in Treg numbers. Here we report the development and in vitro testing of a Treg-inducing synthetic formulation that consists of controlled release vehicles for IL-2, TGF-β and rapamycin (a combination of cytokines and drugs that have previously been reported to induce Treg). We demonstrate that IL-2, TGF-β and rapamycin (rapa) are released over 3-4weeks from these formulations. Additionally, Treg induced in the presence of these formulations expressed the canonical markers for Treg (phenotype) and suppressed naïve T cell proliferation (function) at levels similar to soluble factor induced Treg as well as naturally occurring Treg. Most importantly, we show that these release formulations are capable of inducing FoxP3(+) Treg in human cells in vitro. In conclusion, our data suggest that controlled release formulations of IL-2, TGF-β and rapa can induce functional Treg in vitro with the potential to be developed into an in vivo Treg induction and expansion therapy.
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, United States.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Jhunjhunwala
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Balmert
authors.forename: Giorgio
authors.initials: G
authors.lastname: Raimondi
authors.forename: Eefje
authors.initials: E
authors.lastname: Dons
authors.forename: Erin E
authors.initials: EE
authors.lastname: Nichols
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: Steven R
authors.initials: SR
authors.lastname: Little
mesh_terms: D000328:Adult; D000818:Animals; D003692:Delayed-Action Preparations / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D003692:Delayed-Action Preparations; D007376:Interleukin-2; D053773:Transforming Growth Factor beta1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus