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.
Dr. John Boyd & Dr. Mark Kearns
The Donor Heart After Withdrawal of Life Support
The biggest problem in heart transplantation is the shortage of donor hearts. This shortage results in the death of significant numbers of patients with end-stage heart failure who would have been eligible to receive a new heart. To boost the number of hearts available for transplantation, researchers have been investigating alternative pathways for heart donation. One solution that has significantly increased the number of organs available for lung, liver, and kidney transplantation is referred to as donation after circulatory death (DCD). The biggest problem with DCD hearts is that they are injured because of the donation process and we still can’t precisely identify which heart would be safe or unsafe for recipients. Addressing this problem would remove a major barrier to the use of DCD hearts for transplantation, and reduce the number of people dying unnecessarily on transplant waiting lists.
The main objective of this proposal is to study human DCD hearts on a machine, to find ways of identifying when a heart is too injured, and therefore unsafe to use for a recipient. This approach would allow surgeons to make decisions about a heart’s suitability before committing a recipient to a heart with an uncertain outcome. In most of the world (including British Columbia), DCD hearts are not currently used for transplantation. In fact, these hearts are simply discarded. This represents a lost opportunity for researchers who could put the heart to good use, and make valuable discoveries that would benefit heart failure patients and society.
We had an incredible turn out for our first Celebrate Transplant Research Event! Thank you to everyone who attended and helped make the event such a success. ...
September 12, 2017
A great evening to learn about the exciting and innovative transplant research funded by the Transplant Research Foundation of BC! Attendees heard incredible presentations from leaders in the field of transplantation and networked with transplant researchers, funders and members of the transplant community.