Contagious biomaterials

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Science Translational Medicine  19 Aug 2015:
Vol. 7, Issue 301, pp. 301ec143
DOI: 10.1126/scitranslmed.aad0231

Thousands of patients die each year while waiting for an organ transplant, in part because of incompatibility with available donor organs. Even those lucky enough to find a match must take anti-rejection drugs, which have major side effects such as increased susceptibility to cancer and infection, and often fail over time. To address these challenges, attempts have been made to promote specific immune tolerance to a donor organ through delivery or local activation of regulatory T cells (Tregs). One way to achieve Treg activation in the vicinity of a transplanted organ would be to release the cytokine transforming growth factor–β1 (TGF-β1), but its propensity to promote scarring has hampered its clinical translation.

Taking a cue from activated Tregs themselves, which present a membrane-bound form of TGF-β1 to one another, Yang et al. reasoned that this insoluble version of the cytokine would promote immune suppression without the collateral damage associated with its soluble form. Indeed, the team showed that glass beads and even viable cells with tethered TGF-β1 stimulated differentiation of Tregs in vitro. To truly promote transplant tolerance, however, the induced Tregs should be specific for the donor cells, which would enhance efficacy while limiting broad immunosuppression. TGF-β1–tethered antigen-presenting cells were able to cause T cells to convert to Tregs that were specific for the model antigen chicken ovalbumin (OVA). Interestingly, however, boosting with additional unmodified antigen-presenting cells was necessary to fully activate the OVA-specific Tregs. These results suggest that surface modification with TGF-β1 reduced the cells’ ability to present antigens directly to T cells. Last, the TGF-β1 tethering platform was functionally competent, as demonstrated by suppression of T cell proliferation at similar levels as endogenous Tregs.

Although more studies with human cells and animal models are required to validate this system, this study lays the groundwork for a strategy to confer antigen-specific tolerance to transplanted organs.

E. Y. Yang et al., Engineering an “infectious” Treg biomimetic through chemoselective tethering of TGF-β1 to PEG brush surfaces. Biomaterials 67, 20–31 (2015). [Abstract]

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