Grant: Travel Awards - Institute Community Support

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. We hypothesized that this may be caused by changes in the two main regulators of NK cells, called interleukin-15 (IL-15) and transforming growth factor beta (TGFb). To test this hypothesis, we bred mice with NK cells that either can or cannot produce the main receptor for TGFb, called TGFbRII. These mice were then exposed to low oxygen levels, which causes symptoms of PAH in normal mice. Some of these mice were also treated with IL-15. We then tested our mice for lung and heart function, as well as measured number and function of NK cells. We found that exposure to low oxygen levels caused NK cell numbers to drop, and IL-15 treatment prevented this from happening. Mice that could not produce TGFbRII had similar numbers of NK cells as normal mice, and also had a drop in NK cells when exposed to low oxygen levels. However, the mice that could not produce TGFbRII did not develop symptoms of PAH when exposed to low oxygen levels, unlike normal mice. These studies have helped to better understand how NK cells contribute to PAH. We can now focus our work on changing IL-15 and TGFb signaling in order to restore NK cells, and hopefully treat PAH. Future work will aim to develop a new treatment based on this idea.