There are a group of immune cells in the body termed natural killer cells. These circulate in the blood and lymphatic system. Natural killer cells (or NK cells) are a type of white blood cell used by the body to seek out and kill cells infected with virus, or cells which are foreign, like bacteria and other parasites. They act like the bodies guard dogs, providing continual surveillance, ready to attack anything unusual. All the cells in a human carry a flag on their membrances which is unique to their body. This is called an MHC molecule, and is detectable by the NK cell. The flag tells the NK cell that this tissue is ‘self’ and should not be attacked. On the transplanted organ, there are no recognisable flags, so the NK cell sees the organ as foreign and attacks it. We know that these cells infiltrate or ‘invade’ the transplanted organ soon after surgery, but their specific role in transplant rejection is poorly defined.

We currently have three projects running to determine the role of these cells in the transplanted heart or lung. The first project involves measuring activating receptors. These are the switches which turn the NK cells on and make them attack. The second project involves measuring inhibitory receptors, which as you would imagine, turn the NK cells off. We are correlating this data with the clinical outcome of our patients, in the hope of providing answers to the function of these cells in the rejection process. The third project involves measuring the amount of cytokines inside different types of NK cells (see Cytokines and Cells further down this page). This is a very intricate method, and we hope it will provide us with evidence of how active these cells can be.

The renin angiotensin system (RAS)

The RAS is a pathway by which the body maintains a healthy, working cardiovascular and pulmonary system (heart, lung and blood vessels). It consists of a number of chemicals/proteins that control heart function and blood pressure. RAS has also been shown to play a role in cardiovascular and pulmonary diseases—heart failure, heart attack, angina, sarcoidosis and pulmonary fibrosis. The control of the RAS is from various genes. A gene acts like a blue print that the body uses to make everything, from a cell in your ear to your toe nails. With the RAS, each gene controls a protein- how much to make, and how fast to make it. If the gene has a mutation, it may make more or less of a product, faster or slower. We have examined several of these mutations (polymorphisms), to see how common they are in the transplant population, and how these mutations affect individuals progress following their transplant. Because medication is available which interacts with the RAS, we may identify individuals with genetic risk factors that would benefit from a tailored drug regime. Also, this would reduce the unnecessary exposure of individuals to medication if they are not at risk.

The Cellular Level

In addition to these studies, a useful approach is to look at markers on the surface of cells that are involved in an immune response, i.e. white blood cells. These cells if left unchecked would eventually reject the transplanted organ. Although powerful drugs are used to combat this, most problems arise due to the host’s own immune system. It is one of our aims to look at markers which appear early on in an immune reaction, before the patient begins to reject the transplanted organ, a kind of ‘early warning system’. In order to look at how an immune response develops we look at markers on the patient’s white blood cell surface as they respond to ‘non-self’. This involves labeling them with a fluorescent dye and is known as flow cytometry. We are already beginning to identify markers that may prove to be useful.

Cytokines and Cells

Heart/lung rejection is a complicated process caused by activation of the immune system. The immune system protects the body from harmful substances such as bacteria, virus particles and cancer cells. It can distinguish between “self” and “non-self” and react accordingly. The presence of non-self tissue triggers the immune system to “attack”. The immune response in heart/lung transplantation is seen as rejection.

Immune cells in the body are stimulated or activated by many chemicals, for example cytokines and growth factors. These can influence the severity and duration of an immune response, so are very important in transplant rejection. Another project being undertaken in the Transplant Research Laboratory aims to determine the role of a cytokine called interleukin-15. This causes a type of immune cell (called a natural killer or NK-cell) to mature and activate. NK-cells are a type of white blood cell that can attack non self cells by binding to them and releasing lethal chemicals. They also release cytokines which can activate other immune cells involved in transplant rejection. Drugs are available which can stop interleukin-15 from working, and may help to suppress NK-cell activity. This could be a useful therapy for heart/lung rejection.

Rejection in the Lung

The airways of the lungs are lined by numerous different cell types. These cells are white blood cells (immune cells) that have left the blood vessels and moved into the lung tissue. Depending on the number and type of cells found, these cells can have a protective effect, such as helping to fight infection. They can also be harmful, certain cell types can cause damage to the lungs and are found in high numbers in tissue rejection. The cells can be safely and easily obtained from induced sputum (obtained from nebulising with a saline solution). We are pioneering the use of a specialised technique to study the activity of the immune cells (and the chemicals they release) to gain a better understanding of tissue rejection. Using this information we are looking to see if we can pick up any complications early, before any damage has been done to the transplanted lung. Sputum induction can also be used to identify rejection from other causes of reduced lung function. These include bacteria, virus infection, and reperfusion injury. This enables the physician to administer the appropriate treatment to the patient. We are the first people to identify a link between cell population and changes in lung function following transplantation.

Acute Rejection and VEGF

The human body releases several chemicals from different types of cells. These chemicals can be of benefit or pathological (disease causing). One such chemical is called vascular endothelial growth factor, or VEGF. It helps in forming new blood vessels in the body, which can be bad for cancer patients, but may be good for heart and lung transplant patients with blocked or damaged vessels. However, very little is known about its association with acute rejection and artery disease. Our theory is that new blood vessel formation by VEGF may overcome key complications and improve the well-being of the patient. As with the RAS system (above), certain genes control the regulation of VEGF. Mutations are known which may increase VEGF production. We are investigating the prevalence of these mutations in the transplant population, and relating this information to the amount of VEGF in the blood, with the hope of answering this question.