Research Location: Vancouver General Hospital

About two per cent of men are infertile due to defects in sperm production. In most cases, the underlying cause is unknown. During sperm production, two similar chromosomes – microscopic bodies that carry heredity DNA – pair up and exchange genetic material in a process called meiotic recombination. Recent studies have shown that recombination rates are significantly reduced in infertile men. Infertile men are also more likely to produce sperm with extra or missing chromosomes (called aneuploid sperm). This aneuploid abnormality is the most frequent cause of miscarriage, and among live births, the most common cause of congenital malformations. Kyle Ferguson is using leading edge technology to determine if and how aberrant recombination causes infertility. He is also investigating the recombination patterns that lead to production of aneuploid sperm. This information will help identify genetic mutations that contribute to male infertility, and may lead to new therapies for the condition.

Immune reactions in the central nervous system (CNS) – the brain and spinal cord – differ from other organs. Under normal conditions, the endothelial cells lining blood vessels in the brain act as a “blood-brain barrier” to block the entry of most immune cells into the CNS. In some CNS diseases like multiple sclerosis, and in trauma, stroke and infections, this barrier is compromised. As a result, immune cells migrate to the brain in large numbers causing inflammation, which can lead to serious consequences. Azadeh Arjmandi is studying how immune cells gain access to the brain and spinal cord in infectious, inflammatory and autoimmune diseases. Immune cells called dendritic cells have been found in the central nervous systems of patients with these diseases and their numbers increase with more chronic conditions. Azadeh is examining dendritic cell trafficking across the blood-brain barrier in order to further characterize the molecular mechanisms of inflammation in the brain. This will provide important information about how certain CNS diseases develop and may contribute to more effective treatments.

In the last few decades, new immunosuppressive drugs have improved our ability to treat autoimmune diseases and perform successful transplantation procedures. Despite the success of these drugs, serious side effects including generalized immunosuppression, infections, cancers, diabetes and seizures considerably decrease patients’ quality of life. Recent research in this area has focussed on T regulatory (Tr) cells, a recently characterized subset of white blood cells that have the ability to suppress undesired immune responses, while leaving other aspects of the normal immune system intact. Sarah Allan’s research addresses questions about the molecular and cellular biology of Tr cells. She is investigating how Tr cells arise naturally, the mechanisms by which they suppress immune responses, and how they differ from other types of T cells at the molecular and genetic level. Ultimately, her work will contribute to the development of novel therapies for autoimmune diseases, transplantation, and other pathologies of the immune system.

A growing field in the world of immunology is the study of T regulatory cells (Tregs), a specialized subset of T cells that has the ability to “”turn off”” the immune system after an infection has been cleared. While research has been focused on how Tregs suppress one class of lymphocytes (Th1 and Th2 cells) from proliferating and making molecules that are involved in activating the immune system, the effect of Tregs on the other major class of lymphocytes – the B cells – has received far less attention. Previous experimentation in the laboratory of Grace Lam’s supervisor, Dr. Anthony Chow, has revealed that one injection of Toxic Shock Syndrome Toxin (TSST-1) to cell cultures induces a massive systemic inflammatory response. However, repeated injections of this toxin leads to the activation of Tregs that “”calm down”” the immune response. Grace’s own research has shown that TSST-1 induced Tregs may be able to prevent activation of B cells by suppressing B cell proliferation and/or inducing B cell death. Now, she is studying the mechanisms by which this down regulation occurs. This work holds important promise for understanding and developing more effective treatment for chronic health problems caused by an overactive immune response. Diseases such as systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis, all result from overactive B cells producing excessive amounts of antibodies that damage normal tissue. Grace hopes her research might open the possibility of employing TSST-1 induced Tregs to shut down this abnormal immune response.

The primary reason for someone to undergo a knee replacement is to reduce pain due to arthritis. Unfortunately, some people who have the surgery will have similar, or even more, pain after their knee replacement. It is difficult to predict which patients will have this outcome and it is difficult to treat the pain post-operatively. Much of the pain is likely related to points of high pressure (high contact loads) between the kneecap (patella) and the thigh bone (femur), or unusually stretched soft tissues between the bones. A potential way to minimize pain and other problems following surgery would be to detect these points of high pressure during the operation and make adjustments to the positions of the implants or the tensions of the soft tissues to reduce the contact loads. If the contact loads could be minimized during the surgery, the outcome would be less pain and fewer subsequent surgeries due to wear, loosening or fracture of the components. Dr. Carolyn Anglin intends to reduce pain and improve the outcome of knee replacement surgery by developing a computer-aided system to help identify pressure points during surgery. In addition to performing a cadaver study to investigate the effects of different placements of the artificial components on cadaver specimens, she will review X-rays, patient charts and patient-completed questionnaires to determine the relationship between the placement of components and the resulting quality of life after surgery. Her ultimate goal is to develop a system that can measure the forces between the kneecap and the thigh bone, then display them on a computer screen. This will allow the surgeon to choose the best positions for the components. Such a system could dramatically reduce the incidence of pain and complications following knee replacement surgery.

The recent increase in cases of tuberculosis, mainly due to an association with human immunodeficiency virus, poor living conditions, and the emergence of drug-resistant strains, has been described as a “”global emergency”” by the World Health Organization. New therapeutic strategies are urgently needed and this requires a better understanding of the interaction of the causal agent, Mycobacterium tuberculosis, with the host cells, which include macrophages. Macrophages possess a powerful intracellular killing mechanism and play an essential role in immunity, but they are also the principal targets for mycobacterium. Mycobacterium inhibits the intracellular killing as well as antigen presentation at the cell surface to stimulate adaptive immunity. Dr. Ala-Eddine Deghmane is studying the molecular mechanisms by which pathogenic mycobacteria interferes with macrophage functions. His research aims to advance understanding of the host cells’ failure in resisting to mycobacterial infection and may lead to preventive and therapeutic anti-TB strategies.

Toxoplasma gondii, commonly acquired by eating under-cooked meat, is a particularly successful pathogen that establishes life-long infections with its capacity to infect, replicate and persist chronically within host immune cells. Toxoplasma causes an acute, influenza-like disease that typically becomes a chronic infection. Immuno-suppressed individuals are at risk for developing chorioretinitis (inflammation of the choroid layer behind the retina), blindness and fatal encephalitis. An emerging concept in the immunology of infectious diseases is that persistent pathogens like Toxoplasma establish chronic infections by activating T regulatory cells (Tregs), which are thought to have the ability to selectively suppress immune responses. Dr. Andrew Hall is investigating the immunological basis of Toxoplasma persistence and how this pathogen evolves to promote Tregs. He aims to determine the molecular details governing Treg generation and function, and to establish their role as critical immune regulators of persistent infections. Andrew hopes that results from his research will help to develop novel methods of immunotherapy or vaccines designed to target the regulatory T-cell network in disease and to contribute significantly toward the development of cures.

One of the major problems with organ transplantation is preventing the recipient’s immune system from rejecting the new organ. Currently, patients must follow a strict regime of immunosuppressive drugs for their entire life, which can seriously compromise their immune system and place them at significant risk. The development of a method to induce long-term drug-free acceptance of transplanted tissue and/or organs would have tremendous implications for both patients and the health care system. Research on a newly discovered class of cells called T regulatory cells (Tregs) is focused on finding a better solution to the problem of organ rejection. While researchers know that Tregs are capable of suppressing the activity of other T cells and that they play a significant role in regulating immune response, they do not have a clear understanding of the molecular mechanisms which trigger these actions. Natasha Crellin is studying the characteristics and molecular markers unique to Tregs, aiming to provide further understanding of the differentiation and function of these cells. The goal of her research is to better understand the potential for manipulating the body’s own immune response to replace use of immunosuppressive drugs in preventing organ rejection following transplantation.