The ultimate goal to accomplish a definitive cure for Type 1 Diabetes (T1D) is to replace the lost beta-cell mass while ensuring its long-lasting survival. This could be done by transplantation of pancreatic islets or stem cell-derived insulin-producing cells. However, any replacement will irrevocably succumb to the same autoimmune attack that killed the original beta-cells. Moreover, a mismatch between donor cells and recipient patients adds an allo-graft rejection. Thus, it is of the utmost importance to develop strategies to protect transplanted pancreatic islets from immune attack. Unfortunately, many approaches aiming at restoring tolerance by manipulating immune cells have been tested and, although safe, have shown only limited efficacy. Inflammatory processes, infections or major lifestyle changes can easily alter the balance again towards immune activation. We recently discovered the existence of immune privileged stem cells in the skin and muscle, and found that their ability to resist direct attack by T cells was not dependent on a physical barrier. Instead, it is a cell-autonomous process that allows independent cloaking from immune cells. Here we propose to exploit the molecular circuits controlling this striking phenomenon (that already naturally occurs in our bodies) to provide similar protection to islets for transplantation. We identified a molecular pathway that reduces antigen presentation allowing protection from T cells while preserving enough MHC class I to not trigger a Natural Killer (NK) cell response. Since this mechanism of protection is cell intrinsic, changes in overall immune function should not alter the ability of engineered islets to hide from immune rejection allowing for long-lasting survival.

Disclosure

J.Agudo: None.

Funding

American Diabetes Association (1-20-ACE-08)

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