Date: Saturday, May 2, 2015
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Exhibit Hall E
Background: Regulatory T lymphocytes (Tregs) contribute to transplant tolerance. We have demonstrated that the inhibition of PI3K-mTOR pathway has a major role in the differentiation of naive T cells into functional suppressor Tregs. Objective: To evaluate the effect of the dual PI3K-mTOR inhibitor, PI-103, in human naive CD4+ T cells. Methods: Negatively selected human naive CD4+ T cells were activated with OKT3+anti CD28 and/or OKT3+IL-2 in the presence or absence of different doses of PI-103 and Rapamycin. Multi-parametric FACS analyses were used to measure the expression of early activation markers, lymphokine synthesis, T cell proliferation and differentiation into Tregs or Th17 effector cells. Results: PI-103 induced a significant delay on the expression of early activation markers CD69 and CD25, reduced IL-2 production and decreased proliferation rate in CD4+ T cells. PI-103 increased iTreg conversion from primary human naïve CD4+ T cells and prevented pro-inflammatory Th17 polarization. Analysis of proliferative Ki67+ T cells revealed the preferential targeting of PI-103 to the non-Treg population. Western blot results illustrated the distinct targets of PI-103 suggesting the modulation of feedback loops as a mechanism of the PI-103 dose-dependent increment of mTORC2 activity. PI-103 reduced the glycolytic rate of the cells although showed a delayed metabolic shift. Conclusions: PI-103 shares similar tolerogenic properties with Rapamycin, although distinct molecular mechanism and kinetic responses. Our findings suggest that the dual inhibitory capacity of PI-103 results in the accumulation of iTreg cells and suppression of effector T cells. These results warrant further studies to assess the role of dual PI3K-mTOR inhibition on immunosuppression.
To cite this abstract in AMA style:Vilchez V, Castellanos A, Butterfield D, Mitov M, Hoopes C, Marti F, Gedaly R. Dual PI3K-mTOR Inhibition on Human T Cell Activation, Proliferation, and Differentiation: The First Step in the Development of New Immunosuppressants [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/dual-pi3k-mtor-inhibition-on-human-t-cell-activation-proliferation-and-differentiation-the-first-step-in-the-development-of-new-immunosuppressants/. Accessed September 18, 2021.
« Back to 2015 American Transplant Congress