Targeted ablation of autoreactive T cells without broad immunosuppression.

Maintenance of beneficial T regulatory responses with enhanced Treg to T effector cell balance.

Manipulation of the DNA damage response (DDR) present in activated T effector (Teff) cells to drive preferential elimination via apoptosis.

Minimal off-target effects on islet cell grafts and other cells and tissues thereby allowing for long-term survival of transplanted islets as part of a cure for Type 1 diabetes (T1D).

Type 1 diabetes (T1D) results from insulin insufficiency due to islet death and dysfunction following T cell-mediated autoimmune attack. The technical feasibility of durable, functional autologous islet restoration is progressing such that it presents the most likely long-term cure for T1D but cannot succeed without the necessary counterpart of clinically effective therapeutic strategies that prevent grafted islets’ destruction by pre-existing anti-islet T cells. While advances have been made in broad immunosuppression to lower off-target effects, the risk of opportunistic infections and cancers remains a concern, especially for well-managed T1D patients. Current immunomodulatory strategies in development focus on autologous Treg expansion, treatments to decrease antigen presentation and T effector (Teff) activation, and broad depletion of T cells with or without hematopoietic stem cell transplants. Emerging strategies harnessing the intensified DNA damage response present in expanding T cells, exacerbating their already high sensitivity to apoptosis to abate autoreactive Teff cells.

Type 1 diabetes (T1D)

Pancreatic Islets

Islet graft

T cells

Autoimmunity

Immunosuppression

DNA Damage Response (DDR)

Reactive Oxygen Species (ROS)

p53 Pathway

T cell tolerance

p53 potentiation with checkpoint abrogation

ataxia telangiectasia mutated

autologous hematopoietic stem cell transplants

© 2022 The Authors. Published by Elsevier Inc.