Controlled Release Formulations for Induction and Proliferation of Regulatory T Cells

The absence of regulatory T cells (Treg) is a hallmark for a wide variety of disorders, including autoimmune disorders, dermatitis, periodontitis, and transplant rejection. Increasing local Treg numbers is a potential treatment option, but current methods for in vivo Treg expansion rely on biologic therapies, which are not specific to Treg cells and are associated with many adverse side effects.

Quantitative analysis of the fold change in % FoxP3+ iTreg after in vitro re-stimulation either in the absence (A) or presence (B) of Treg-inducing factors, including cytokines and small molecules, demonstrating that iTreg generated in the presence of rapamaycin are more stable in long-term in vitro cultures.

Description

Researchers have developed a Treg-inducing synthetic formulation consisting of controlled release vehicles for IL-2, TGF-β, and rapamycin, a combination of cytokines and drugs previously reported to induce Treg proliferation as an alternative strategy to achieve in situ Treg expansion as a potential treatment option. Treg induced in the presence of these formulations express the canonical markers or Treg and suppressed naïve T cell proliferation at levels similar to soluble factor-induced Treg as well as naturally occurring Treg. Most importantly, these release formulations are shown to be capable of inducing FoxP3+ Treg in human cells in vitro. This method supports the future development of controlled release formulations that can induce function Treg in vitro with the potential to develop in vivo Treg -specific induction and expansion therapy as an off-the-shelf therapeutic for creating a local immunosuppressive environment and increasing the presence of Treg at sites of inflammation.

Applications

· Treating contact dermatitis
· Treating periodontitis
· Preventing graft rejection in skin and composite tissue transplantations
· Treating autoimmune disorders
· Treating other diseases where immune homeostasis is lost and needs to be restored
· Off-the-shelf therapeutic for increasing the presence of Treg and creating an immunosuppressive environment at localized sites

Advantages

· Specific for inducing the proliferation regulatory T cells while minimizing off-target effects
· First technology with the potential to deliver the soluble factors necessary for regulatory T cell induction in vivo in a sustained and controlled manner

Invention Readiness

In vitro data

IP Status

https://patents.google.com/patent/US20200405644A1

Related Publication(s)

Greene, A. C., Shehabeldin, M., Gao, J., Balmert, S. C., Ratay, M., Sfeir, C., & Little, S. R. (2022). Local induction of regulatory T cells prevents inflammatory bone loss in ligature-induced experimental periodontitis in mice. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-09150-8

Bassin, E. J., Buckley, A. R., Piganelli, J. D., & Little, S. R. (2020). TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model. PLOS ONE, 15(9), e0239396. https://doi.org/10.1371/journal.pone.0239396

Fisher, J. D., Balmert, S. C., Zhang, W., Schweizer, R., Schnider, J. T., Komatsu, C., Dong, L., Erbas, V. E., Unadkat, J. V., Aral, A. M., Acharya, A. P., Kulahci, Y., Turnquist, H. R., Thomson, A. W., Solari, M. G., Gorantla, V. S., & Little, S. R. (2019). Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation. Proceedings of the National Academy of Sciences, 116(51), 25784–25789. https://doi.org/10.1073/pnas.1910701116

Ratay, M. L., Balmert, S. C., Acharya, A. P., Greene, A. C., Meyyappan, T., & Little, S. R. (2017). TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-17869-y

Balmert, S. C., Donahue, C., Vu, J. R., Erdos, G., Falo, L. D., Jr., & Little, S. R. (2017). In vivo induction of regulatory T cells promotes allergen tolerance and suppresses allergic contact dermatitis. Journal of Controlled Release, 261, 223–233. https://doi.org/10.1016/j.jconrel.2017.07.006

Jhunjhunwala, S., Balmert, S. C., Raimondi, G., Dons, E., Nichols, E. E., Thomson, A. W., & Little, S. R. (2012). Controlled release formulations of IL-2, TGF-β1 and rapamycin for the induction of regulatory T cells. Journal of Controlled Release, 159(1), 78–84. https://doi.org/10.1016/j.jconrel.2012.01.013