Alberta Innovates- Health Solutions

Killers, whether good guys or bad guys, and why they do what they do are usually the fodder for police detectives and big-screen action films.

For one Heritage researcher at the University of Alberta, Dr. Hanne Ostergaard, killers hold a fascination that has nothing to do with the macabre. Dr. Ostergaard's work is focused entirely on life-and-death dramas enacted in our bodies, where "good guy" killer cells protect us from invaders, mutated cells gone amok, and other "bad guys". How these killer cells, a.k.a. cytotoxic T-cell lymphocytes, know what to kill and what to spare is the crux of Dr. Ostergaard's research. Her answers in the area of cell signalling may contribute to the growing store of knowledge scientists are compiling about our body's ability to resist or succumb to disease.

Two main types of killer cells exist in our immune system: killer T-cells and natural killer cells. Killer T-cells are true immune cells: they have to be primed with an antigen a substance that mimics or contains a de-armed piece of a bad cell before they work. The T-cells remember the antigen next time they see it and mobilize to defend the body the reasoning behind vaccinations with a type of immunological memory. Natural killer cells have no immunological memory: they are ready at any time to attack any type of cell.

Dr. Ostergaard is mainly interested in killer T-cells, specifically in how they seek out an abnormal cell. "I am not interested in the killing mechanism per se," she says. "I want to find out how the T-cell crawls around in tissues, and what happens when it comes in contact with an antigen a tumour cell or a virally infected cell. There are a number of molecular interactions that must occur before the tumour cell or virally infected cell can be eliminated."

One of the specific actions that happens is that receptors on T-cells that "see" an antigen are too weak to effectively bring together the T-cell and the antigen. Other molecules are involved in the interaction, including one group called integrins. Expressed by all cells in the body and in many different forms, integrins are involved in forming tissue. They are the molecules that bind to collagen, for example, in wound healing. Some integrins are unique to T-cells, and some are shared with other cells but have unique functions in each. Just how integrins bind killer T-cells and antigen targets together, and involve other signalling and messenger molecules in the process, is a focus of Dr. Ostergaard's work. She is also pursuing which of these signals tell a Killer T-cell to kill a target cell.

One of the approaches scientists are now taking with cancer is to design vaccines that target diseased cells. In order for vaccines to be useful, it is crucial to determine what is the minimum requirement for the vaccine to work. "For example," says Dr. Ostergaard, "we know it's not enough for a T-cell just to see the antigen; other interactions are involved."

One approach has been to take actual tumour cells and engineer them to express a particular molecule called B7-2, a molecule important in T-cell recognition of an antigen, and re-introduce the tumour into the patient. The hope is that killer T-cells will see the B7-2 and kill not just the tumour cells with the B7-2 but the other tumour cells as well. Although this appears to work well for some tumours, Dr. Ostergaard points out that T-cells may require different sets of molecules to kill different tumours, because immunological memory is based on complex chemical steps. One way to improve such a vaccine is to identify some of the molecules that are involved in the interaction with the target cells. "By defining particular interactions, we should be able to improve on vaccine development," she says.

Dr. Ostergaard's work also has implications in the area of autoimmune diseases. Drugs needed by people with autoimmune diseases, or by people who have received organ transplants, suppress the immune system, often allowing cancers and other diseases to develop. The signalling research she does could lead to drugs that would specifically target T-cell activation. If specific drugs could be designed to keep the disease-causing T-cells turned off, many people currently on immunosuppressive drugs would enjoy a better quality of life.

She is also looking at the mechanisms by which tumour cells use sugars on their cell surfaces to disguise themselves from the immune system. Certain drugs currently in clinical trials prevent tumour cells from using the sugars, but scientists aren't sure why these work. Dr. Ostergaard is studying exactly what the T-cell needs to see on the tumour cells in order to figure out how the drugs work.

Dr. Hanne Ostergaard is a Heritage Senior Scholar in the Faculty of Medicine at the University of Alberta. She also receives funding from the Medical Research Council and the National Cancer Institute.

Dr. Stuart Edmonds is a Heritage- funded Post-doctoral Fellow, and Lawrence Puente is a Heritage-funded student working in Dr. Ostergaard's laboratory. Heritage-funded students Chris Arendt and Nancy Berg recently completed their PhD degrees in the Ostergaard lab.