Induction of Allograft Vasculopathy by CD8+ T cells under conditions of immunosuppression.

Although most transplanted hearts survive well for the first year (95% survival), there is a chronic ongoing rejection process which results in heart transplant malfunction in about 50% of patients by 10 years post transplant. This process continues such that 20 year survival is less than 10%. Given that the average age of a heart transplant recipient in Canada is 50 years old this is a significant clinical problem that has yet to be resolved. Unfortunately, the anti-rejection drugs that work so well to prevent early transplant rejection do not prevent this late response. This is primarily because the biological basis of the two responses is quite different. Late transplant rejection is due to a growing lesion in the inside of the coronary arteries that eventually results in blockage. This lesion is caused by the immune response and is called allograft vasculopathy. Because it looks somewhat like naturally occurring arteriosclerosis it is sometimes called allograft arteriosclerosis. A significant limitation to successful development of novel therapies for allograft vasculopathy is the uncertainty regarding the nature, origin and mechanism of development of the lesion. In our experiments in mice we have shown that immunosuppressive drugs (similar to the kind used in human transplant patients) block the activities of some parts of the immune system but not others. The primary part to escape these immunosuppressive drugs are the CD8+ T cells. In our last grant supported by the CIHR we showed that these CD8+ T cells are responsible causing allograft vasculopathy under conditions of clinically relevant immunosuppression. In this renewal project we are now trying to understand how these CD8+ T cells cause this lesion and the resulting loss of transplanted hearts. In the end our aim is to achieve a sufficient understanding of this process to be able to intervene with therapeutic agents to shut down this disease.