Controlled release formulations of IL-2, TGF-β1 and rapamycin for the induction of regulatory T cells

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-beta and rapamycin (a combination of cytokines and drugs that have previously been reported to induce Treg). We demonstrate that IL-2, TGF-beta and rapamycin (rapa) are released over 3-4 weeks from these formulations. Additionally, Treg induced in the presence of these formulations expressed the canonical markers for Treg (phenotype) and suppressed na ve 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-beta and rapa can induce functional Treg in vitro with the potential to be developed into an in vivo Treg induction and expansion therapy. (C) 2012 Elsevier B.V. All rights reserved.