Grant: CIHR Fellowship

Pulmonary arterial hypertension (PAH) causes narrowing and loss of blood vessels in the lungs, leading to increased stress on the heart and death by heart failure. Treatments for PAH are expensive and provide little benefit to the patient in terms of symptoms and survival. For many years, PAH has been associated with dysfunction in the immune system. Recently we have discovered that Natural Killer (NK) immune cells are reduced in number and impaired in function in PAH. Normally, IL-15 is needed for NK cell function and survival, while TGFb alters NK cell function and blocks the effects of IL-15. However, we and others have found that IL-15 and TGFb signaling is altered in PAH patients and in animal models of PAH. In the pregnant uterus and cancerous tumors, NK cells change their function to help form blood vessels that allow the fetus or tumor to grow. We believe that something similar occurs in PAH lungs, and NK cells are "tricked" into making the diseased lungs worse. To test this hypothesis, we have bred mice with NK cells that either can or cannot produce the main receptor for TGFb, called TGFbRII. These mice will be exposed to low oxygen levels, which will cause symptoms of PAH in normal mice. We will then test our mice for lung and heart function, as well as measure number and function of NK cells. We would expect the mice with NK cells that cannot produce TGFbRII will not develop PAH when exposed to low oxygen, and will have normal heart, lung and NK cell function. Furthermore, we will test a new treatment made by HCW Biologics which both stimulates IL-15 signaling and blocks the actions of TGFb (known as HCW9218). We will induce PAH in rats using two different methods and then treat the rats with HCW9218. We expect HCW9218 treatment will cure the rats of their PAH symptoms. These studies will help to better understand how NK cells contribute to PAH and will further develop a new treatment based on this idea.