Grant: Travel Awards - Institute Community Support

Chronic rejection is the number one cause of death in heart transplant patients after one year. A new inflammatory protein measured in the bloodstream of transplant patients, called Granzyme K (GzmK), has been shown to be significantly elevated in patients suffering from chronic organ rejection. GzmK is a protein from a family of enzymes known as granzymes that are typically secreted by immune cells. Granzymes act as molecular scissors that cut up other proteins in various ways. Downstream effects of granzyme activity results in inflammation, cell death and organ dysfunction. We had recently discovered that GzmK is involved in the earliest stages of human organ rejection by promoting inflammation and immune damage specifically to the transplants blood vessels. Following immune damage and activation, the cellular community within the blood vessel begins to change as some cells begin to die while others begin to multiply and grow rapidly. This rapid growth inside the wall of the artery, known as hyperplasia, begins to narrow the vessel and obstruct blood flow. Ultimately, the transplanted organ is deprived of oxygen and fails. We studied this protein in mice using a model of organ rejection that simulates chronic heart rejection in humans. This is accomplished by transplanting a segment of abdominal aorta, the major blood vessel in the belly, from one mouse to a recipient mouse of a different genetic strain. Recipient mice were either genetically normal, or they lacked the gene to produce GzmK (GzmK-KO), thereby modelling a drug that targeted the protein. GzmK-KO mice had significantly less chronic rejection and blood vessel narrowing than the genetically normal mice. There was also less inflammation and hyperplasia in the GzmK-KO transplants. As a result, we can conclude that GzmK is a likely inflammatory player in chronic rejection and that it will ultimately serve as a future drug target to increase the survival and quality of life of heart transplant patients.