Diabetes and other autoimmune endocrine diseases
Our understanding of the causes and possible treatments for Type 1 Diabetes (T1D) has been profoundly limited by a lack of models that recapitulate human T1D. As the foundation for such a model, we have differentiated human induced pluripotent stem cells into functional β cells (hiPSC-β cells) that can reverse diabetes in mice. Herein, we propose an in vitro platform can model human T1D using hiPSC-β cells. We then sought to discover the genetic modifications of the T1D hiPSC-β that protect them from an immune response.
A cell-type specific, donor-matched response against the hiPSC-β but not the hiPSC-α cells was achieved in vitro. Specifically, co-culturing donor-matched hiPSC-β cells and PBMCs resulted in activation of the effector cells, as assayed through cytokine secretion, T cell activation and specific killing of the hiPSC-β cells. We sought to determine whether the cell killing was mediated by T cell receptor (TCR) engagement. First, we incubated the targets cells with an HLA-class I blocking antibody and second, we used a transwell co-culture system where there was no contact between the immune and hiPSC-β cells. Both experiments prevented T cell activation, confirming the TCR engagement hypothesis.
Having confirmed that we are able to recapitulate aspects of T1D immune attack in vitro, we are interested in the ability of protecting hiPSC-β cells to avoid recurrent autoimmunity. We have generated gene modified hiPSC-β’s that trigger a reduced immune response in vitro. Collectively this data suggests that we can immunoprotect and test hiPSC-β cells in vitro before autologous transplantation.