Use of DNA-PKcs inhibitors to reduce immune response in a subject or reduce the risk of graft rejection in a transplant patient
• Reduce allograft rejection
• Reduce inappropriate T-cell responses associated with various diseases (e.g. allergies and autoimmune diseases
Transplant immunosuppression has a market size of approximately $5 billion per year in the United States. In spite of the effort put forth to minimize the immune response in these patients, allograft rejection remains a significant and expensive issue. Reducing the immune response in transplant patients would improve transplant success rate and reduce the overall economic burden associated with these procedures.
The inventors have identified pharmaceutical compositions that are DNA-PKcs inhibitors. These inhibitors can prevent IL-2 production in T-cells, which makes the compound remarkably useful for immunosuppression in the transplant setting.
Reducing the production of IL-2 has the potential to decrease both cell-mediated and humoral immunity that leads to graft rejection. The inventors have demonstrated that DNA-PKcs knockout mice do not reject skin grafts, which
supports the hypothesis that DNA-PKcs inhibitors may be valuable for limiting graft rejection. Additionally, the inventors have demonstrated that DNA-PKcs inhibition does not affect PD-1 expression. This is important because PD-1 suppresses the immune system and blocking PD-1 may promote graft rejection. Finally, the inventors have shown that DNA-PKcs inhibition promotes T-helper type 1 cell differentiation.
Knockout mouse model supports the mechanism of action