To cure Type 1 Diabetes (T1D) is necessary to restore the lost beta-cells while ensuring their long-lasting survival. This could be done by transplantation of primary or stem cell-derived islets. 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 against transplanted cells. 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. We recently discovered the existence of immune privileged tissue-resident stem cells and found that their ability to resist direct attack by T cells was not dependent on a physical barrier. Instead, it was a cell-autonomous process that allowed cloaking from immune cells. 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. We have exploited such molecular circuits to provide similar protection to beta-cells for transplantation. Since this mechanism of protection is cell intrinsic, changes in the immune system should not jeopardize their survival. Preliminary data engineering beta-cell-like cells demonstrated that targeting this pathway leads to protection both in the Non-Obese Diabetic (NOD) model of T1D as well as in a model of CD8+ T cell-mediated autoimmune attack against beta-cells. Here we report novel candidate genes to engineer beta-cells for transplantation that can allow them to become immune silent.

Disclosure

J.Agudo: None. X.Sanchez: None.

Funding

American Diabetes Association (1-20-ACE-08 to J.A.)

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