Granzyme K in Allograft Vasculopathy and Expression in Cardiac Tissue

Heart Failure is a common disease affecting at least 23 million people world-wide and its occurrence is increasing given that more people are surviving heart diseases. 1 in 5 people over 40yrs are predicted to develop heart failure with a death rate of 50-60% over 5 years. Heart transplantation is the gold-standard treatment in patients with end stage heart failure. Transplant rejection is the major limiting factor in long term survival of transplant patients. There are 2 types of immune rejection; early (acute) and late (chronic). Late rejection is dominated by immune damage to the blood vessels that feed the transplanted heart. As a result, scar tissue narrows these blood vessels and the heart   muscle is deprived of oxygen and nutrients and the heart ultimately fails.

Immune cell infiltration is one of the earliest steps in late rejection. Immune cells can cause damage to the transplanted heart by secreting protein-degrading enzymes known as Granzymes. These so-called proteases damage the inner layer of the blood vessels of the transplanted heart causing them to die.

Granzyme K (GzmK) has been shown to be highly elevated in patients with late rejection and causes significant inflammation in blood vessels. Using a mouse model of human transplant rejection and mice that genetically lack GzmK, we will test whether GzmK deficiency results in reduced late rejection and inflammation. This project will provide key proof of concept data as to whether to pursue GzmK as a future drug target for attenuating chronic transplant rejection. Ultimately our goal is to reduce the impact of late rejection and increase transplant patient survival.