TY - JOUR
T1 - Controlled release formulations of IL-2, TGF-β1 and rapamycin for the induction of regulatory T cells
AU - Jhunjhunwala, Siddharth
AU - Balmert, Stephen C.
AU - Raimondi, Giorgio
AU - Dons, Eefje
AU - Nichols, Erin E.
AU - Thomson, Angus W.
AU - Little, Steven R.
N1 - Funding Information:
This publication was made possible by Grant KL2 RR024154 (to SRL) from the National Center for Research Resources (NCRR, a component of the National Institutes of Health (NIH)), and NIH Roadmap for Medical Research, as well as Grant 1R56DE021058-01 from the National Institute of Dental and Craniofacial Research (NIDCR, a component of the National Institutes of Health (NIH)) (both to SRL). This work was also supported by NIH grant R01 AI67541 (to AWT) and by the Arnold and Mabel Beckman Foundation (to SRL). GR is in receipt of an American Heart Association Grant-in-Aid and the Starzl Transplantation Institute Joseph Patrick Fellowship.
PY - 2012/4/10
Y1 - 2012/4/10
N2 - 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 3-4 weeks 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.
AB - 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 3-4 weeks 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.
KW - Controlled release PLGA
KW - IL-2
KW - Induced regulatory T cell
KW - Rapamycin
KW - TGF-beta
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U2 - 10.1016/j.jconrel.2012.01.013
DO - 10.1016/j.jconrel.2012.01.013
M3 - Article
C2 - 22285546
AN - SCOPUS:84859494040
SN - 0168-3659
VL - 159
SP - 78
EP - 84
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -