Tu132 - Induction of Antigen-Specific Immune Tolerance in Type 1 Diabetes by Antigen-Expressing Red Cell Therapeutics

We are developing allogeneic Red Cell Therapeutics (RCT) that are genetically engineered in vitro from hematopoietic stem cells to express antigenic peptides with the goal of inducing antigen-specific tolerance in T cell-mediated diseases such as type 1 diabetes (T1D).  For T1D mechanistic and POC studies we used both the BDC2.5 adoptive transfer model and the spontaneous T1D NOD model.   

We show in the BDC2.5 model that a single treatment with mouse RBCs (1e9) carrying a peptide agonist of BDC2.5 T cells (mRBC-p31) confers long term protection from diabetes (90+ days). Even longer protection (160 days) was observed when mice were treated 3 times with a 10-fold lower dose.  Moreover mRBC-p31 administered after insulitis has set in were equally effective in halting the disease for at least 120 days. Tolerance induced by mRBC-p31 was resistant to rechallenge with BDC2.5 T cells, suggesting the emergence of regulatory T cells.  Indeed, using single cell RNA-Seq we observed that mRBC-p31 mediated tolerance involved induction of both Foxp3+ and Tr1 regulatory T cells and additionally uncovered an anergic population. In the NOD model, two treatments at weeks 10 and 14 with mRBCs containing two epitopes from insulin and the 2.5HIP hybrid insulin peptide delayed disease induction up to 25 weeks of age, a finding that supports the notion that the RBC-based therapy induces bystander suppression in this complex disease model.                

In summary, we report on the potential utility of antigen-expressing RCTs as a novel modality to treat T1D and potentially other HLA-linked autoimmune diseases.