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

• Published in: Journal of controlled release 2012-04, Vol.159 (1), p.78-84
• Main Authors: Jhunjhunwala, Siddharth, Balmert, Stephen C., Raimondi, Giorgio, Dons, Eefje, Nichols, Erin E., Thomson, Angus W., Little, Steven R.
• Format: Article
• Language: English
• Subjects: Adult; adverse effects; Animals; autoimmunity; Biological and medical sciences; cell proliferation; Controlled release PLGA; Delayed-Action Preparations - pharmacology; dermatitis; drugs; General pharmacology; graft rejection; Humans; IL-2; Induced regulatory T cell; interleukin-2; Interleukin-2 - pharmacology; Lymph Nodes - cytology; Medical sciences; Mice; Mice, Inbred C57BL; periodontitis; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; phenotype; Rapamycin; Sirolimus - pharmacology; Spleen - cytology; T-lymphocytes; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; TGF-beta; therapeutics; TOR Serine-Threonine Kinases - antagonists & inhibitors; transforming growth factor beta 1; Transforming Growth Factor beta1 - pharmacology
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2012.01.013

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. [Display omitted]