Date: Tuesday, June 5, 2018
Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
Location: Room 606/607
Clinical trials of adoptively transferred regulatory T cells (TRegs) have been hindered by the short lifespan of these transferred TRegs. Systemic injection of low-dose interleukin (IL)-2 preferentially stimulates the high-affinity trimeric IL-2 receptor, abundantly expressed on TRegs, leading to greater cellular expansion. However, cytotoxic CD8 T cells and NK cells are also significantly expanded by this strategy. Here, we describe novel engineered TRegs conjugated with IL-2 nanogel (NG) particles before adoptive transfer. The NG's gradual secretion of IL-2 in vivo selectively promotes TReg viability, and is engineered by reversibly crosslinking carrier-free protein using a bis-N-hydroxy succinimide (NHS) crosslinker. Incorporation of monoclonal antibodies against the highly-expressed cell surface phosphatase CD45 acts as an anchor to retain the NG on TRegs. Upon TReg activation, increased reduction activities lead to the progressive degradation of the crosslinker and sustained IL-2 release. We show that the coupling efficiency of NG to magnetically-isolated murine TRegs is above 80% (n=5 experiments; ****P<0.0001), and that NG-conjugated TRegs maintain their FoxP3 expression after coupling compared to the control (CT) TRegs (99% vs. 92%, CT vs. NG; n=5 experiments; P=n.s.). To test TReg homeostasis in vivo, Immunodeficient RAG1-/- mice received BALB/c skin transplants and were injected with 1:1 TRegs:CD8 T cells from mismatched C57BL/6 donors to induce alloimmunity. Seven days post adoptive transfer, a two-fold increase in TRegs was observed in the spleens of mice that received NG TRegs compared to CT TRegs (n=11/group; **P<0.01). Furthermore, contrary to when IL-2 is systemically injected, we saw a more than three-fold increase in TRegs:CD8 and TRegs:NK ratios in the NG-treated mice (n=11/group; *P<0.05). In a GvHD model, the adoptive transfer of NG TRegs reduced disease progression compared to CT TRegs. In summary, we show that the IL-2 NG T-cell conjugation strategy can efficiently and specifically improve the in vivo expansion of transferred TRegs while sparing CD8 and NK T cells, thus improving the therapeutic efficacy of TRegs and IL-2.
CITATION INFORMATION: Eskandari S., Bandeira Melo M., Assaker J., Mansouri A., Cai S., Al Dulaijan B., Mohamed M., Irvine D., Azzi J. Engineering Regulatory T Cells with Interleukin (IL-)2 Nanogel for Improved Alloimmune Suppression Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Eskandari S, Melo MBandeira, Assaker J, Mansouri A, Cai S, Dulaijan BAl, Mohamed M, Irvine D, Azzi J. Engineering Regulatory T Cells with Interleukin (IL-)2 Nanogel for Improved Alloimmune Suppression [abstract]. https://atcmeetingabstracts.com/abstract/engineering-regulatory-t-cells-with-interleukin-il-2-nanogel-for-improved-alloimmune-suppression/. Accessed July 17, 2019.
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