Memory T cells (Tm) are difficult to control post-transplantation and account for early rejection episodes. Additionally, therapies exerting local immunosuppression by targeting an allograft, while reducing side-effects offer great potential. Novel Targeted Rapamycin Micelle (TRaM) nanoparticles with pH-triggered release of rapamycin at endothelial cells were used to assess Tm function when compared to naïve effector cells in varying oxygen tension environments.

Methods: TRaMs were conjugated to fluorophores and arginine-glycine-aspartate for tracking and targeting to α v β 3 integrins. Mouse cardiac endothelial cells (MCEC) from FVB mice were inoculated into allogeneic C57/BL6 mice for 21 days. Splenic Tm of host mice were cultured with MCEC for 72 hours. As a control, splenic T cells from naïve C57/BL6 mice were cultured with MCEC. Cultures were exposed to both a hypoxic chamber, mimicking organ ischemia, and normoxic conditions. ELISA for IFN-γ was performed on culture supernatants.

Results: Tm produced marked amounts of IFN-γ when cultured with MCECs in hypoxic (40.54 +/- 3.38 pg/ml) and normoxic (83.76 +/- 9.8 pg/ml) conditions. Tm production of IFN-γ was significantly reduced when cultures were treated with TRaM in hypoxic and normoxic settings (17.95 +/- 1.389 pg/ml and 32.70 +/- 6.929 pg/ml; p ≤ 0.0001.) Cultures treated with TRaM showed a therapeutic effect similar to free rapamycin.

Conclusions: TRaMs have proven beneficial as a local immunosuppressive device. These data support the ability of TRaM to also blunt the function of Tm in the face of ischemia as well as normal oxygen tension.

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