Borrelidin: a novel therapeutic agent for treatment of inflammatory diseases

Inflammation is the body's normal physiological response to injury, infection or foreign substances. While the ability to mount an inflammatory response is essential for survival, the ability to control inflammation is also necessary for health. Inflammatory diseases such as rheumatoid arthritis, osteoarthritis, Chrohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, allergies, septic shock, atherosclerosis and many others are a group of disorders characterized by uncontrolled or excessive inflammatory responses. Often, clinical intervention is required to prevent tissue damage and organ dysfunction in these disorders. While there have been advances in anti-inflammatory therapies over the years, long term use of steroidal and non-steroidal anti-inflammatory drugs (NSAIDS,) is limited due to drug-induced toxicities such as stomach ulcer, gastric erosion, exacerbation of asthma and nephrotoxicity. Therefore, the identification of novel agents that can effectively suppress inflammatory responses without associated long term toxicities represent a major unmet medical need. One of the key ways that the body controls inflammation is through the expression of immunoregulatory enzymes. An example of this natural immunoregulation occurs in pregnant mammals: cells of the placenta that surround the fetus express an immunoregulatory enzyme called indoleamine 2,3-dioxygenase (IDO). IDO expression protects the fetus from being attacked by the mother's immune system. Earlier research has revealed that the small molecule drug, borrelidin, could be used to specifically mimic the signalling effects induced by IDO expression and suppress the action of inflammatory cells. Nadya Ogloff's research builds on this evidence by providing pre-clinical proof-of-principle data to support further development of borrelidin as a potent immunosuppresive agent for treatment of inflammatory diseases.

The mechanism by which SOCS3 mediates IL-10 inhibition of macrophage activation

Inflammation is a protective response generated by immune cells against infection. However, when inflammation becomes unregulated within the body, it can cause diseases. A key anti-inflammatory regulator of immune cells is a cytokine (a type of hormone), called interleukin-10 (IL-10). The importance of IL-10 in regulating immune cell function is illustrated by the fact that many tumour cells and intracellular pathogens produce or elicit production of IL-10 for their survival. A main target of IL-10 is macrophages. Activation of macrophages by interferons, or bacterial cell products such as lipopolysaccharide (LPS), induces a number of immunologic responses including production of pro-inflammatory mediators such as the cytokine TNF. IL-10 is able to suppress these events by interfering with pathways utilized by LPS, but its mechanism is unclear. Previous research on the intracellular signal transduction pathways utilized by IL-10 has shown that an important component is a protein called SOCS3 which is thought to target specific proteins for degradation. In order to understand how IL-10 uses SOCS3 to inhibit macrophage activation, Tsz Ying Sylvia Cheung’s research is focusing on proteins that interact with SOCS3 in cells stimulated with IL-10. Identification of these proteins will allow for a further research focus on understanding the role they play in macrophage activation and why they are targeted by IL-10. Developing a clear understanding of the mechanism by which IL-10 regulates the network of intracellular signal transduction pathways will better enable the development of therapeutics mimicking the beneficial anti-inflammatory effects of IL-10, and allow for the development of strategies to counter the immunosuppressive effects of certain tumours and immune cell pathogens.

Functional characterization of T cells and T regulatory cells in Inflammatory Bowel Disease

Crohn's disease and ulcerative colitis, two forms of Inflammatory Bowel Disease (IBD), are disorders believed to be caused by the cells of the immune system mistakenly attacking the tissues of the digestive tract. This phenomenon, known as autoimmunity, leads to massive inflammation of the affected area and consequently causes severe pain, diarrhea, bleeding and other debilitating symptoms. With few treatments and no cure to date, this disease continues to impact both the general population and our health care system. Current research suggests that the inflammation associated with IBD is caused by self-reactive immune cells called T cells that attack the gut tissue, along with a loss of T regulatory cells (Tregs), which act to 'turn off' the immune system. Furthermore, flagellin, a protein present on all motile bacteria including the microflora found within the intestine, may also contribute to the establishment of IBD associated inflammation through its influence on T cells and Tregs. Indeed, studies have shown an immune response is generated against flagellin in 50 percent of patients with Crohn’s disease. However, the nature of these responses remain largely uncharacterized. Megan Himmel's research aims to optimize a novel method of identifying T cells and Tregs which are specifically reactive to flagellin, in order to study their function and their possible contribution to the pathogenesis of IBD. This work may lead to a novel diagnostic marker for IBD, as well as further insight into the immune mechanisms contributing to this disease. Furthermore, Ms. Himmel’s research will provide important insight into the overall role of T cells and Tregs in the establishment and progression of IBD in humans, with the ultimate goal of establishing methods to therapeutically manipulate the balance of pathogenic versus regulatory immune responses.

Regulation and Function of Human T helper 17 Cells

Immune system homeostasis is determined by the balance between responses that control infection and tumour growth and reciprocal responses that prevent inflammation and autoimmune diseases. Dysregulated immune responses, such as those that occur with autoimmune disorders and organ rejection, result when and an individual’s immune system mistakenly attacks normal cells. Current treatment approaches involve following a strict regimen of immunosuppressive drugs for the duration of a patient’s life. These treatments, however, seriously compromise an individual’s ability to fight infection and are associated with an increased risk of developing cancer. Sarah Crome’s research has two main focuses. The first is on the regulation and function of a newly discovered class of inflammatory white blood cells (WBC), termed T helper 17 (Th17) cells, which serve an essential function in host defense against extracellular pathogens. While being key players that protect the body from harmful pathogens, Th17 cells are also linked to inflammatory diseases including rejection of transplanted organs and cells, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Therefore, it is essential to understand the mechanisms that regulate this cell population in order to be able to treat patients with dysregulated immune responses. Secondly, Ms. Crome and colleagues are examining interactions between Th17 cells and another WBC population, termed T regulatory (Treg) cells, which serve a protective function by suppressing harmful immune responses. Currently, Treg cells are being clinically tested as a cell-based therapeutic alternative to immunosuppressive drugs. However, the diseases where Treg cell-based therapies are being investigated are the same diseases that are associated with Th17 cell activity. Therefore, understanding the interactions between these two cell populations will be essential for clinical based studies of Treg cells, and the development of improved therapies.

Imaging Early Micro-Structural Bone Changes in the Rheumatoid Hand: A High Resolution-Peripheral Computed Tomography (HR-pQCT) Study in People with Newly Diagnosed RA

Rheumatoid Arthritis (RA), affects one percent of the general population. Radiographic (x-ray), evidence of bone thinning (osteoporosis), and bony destruction (erosions), in the bone surrounding inflamed joints is an important diagnostic criterion for RA. These changes are present in the hands and feet of 80 percent of people with RA and can have profound implications with regard to the development of hand deformity, functional limitations and the need for restorative joint surgery. Early presentation of destructive bone changes is associated with a more aggressive disease progression and evidence suggests that starting disease-modifying anti-rheumatic drugs (DMARDs), soon after the diagnosis of RA may help prevent some people from developing bone damage. However, not all people with early RA respond to DMARDs, with ‘non-responders’ requiring more aggressive interventions including trials of combinations of different drug treatments or biologic response modifier drugs. Unfortunately, the time delay associated with implementing effective treatment in people with more aggressive or resistant RA means they are at greater risk for permanent bone damage. Current clinical imaging with Dual X-ray Absorptiometry (DXA), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI), can detect bone damage earlier than x-ray but these tools are not able to identify the initial ‘micro-structural’ changes in the early RA hand. Dr. Lynne Feehan is characterizing early ‘micro’ structural hand bone changes over a two-year period in people with newly diagnosed RA using High Resolution – Peripheral Quantitative Computed Tomography (HR-pQCT), a promising new imaging system capable of imaging the very fine bone internal ‘micro’ detail at a resolution equivalent to the diameter of a human hair. The results of Dr. Feehan’s research could improve patient’s early access to appropriate therapy, and thereby improve their quality of life.

Effect of cam-type deformity associated with femoroacetabular impingement on hip mechanics

Hip osteoarthritis (OA) is a painful condition affecting 4.4 per cent of the population aged 55 and older. Currently, there are very limited treatment options and no known cure for OA. Improving prevention and treatment of early hip OA requires a thorough understanding of the joint mechanics and how these mechanics affect the initiation and progression of the disease. Hip OA can either be primary (occurs with no previously known cause) or it can be secondary to a known deformity. It has recently been hypothesized that most “”primary”” cases are actually caused by small deformities in the joint that were previously unnoticed. One deformity that has been found to have a strong correlation with hip OA is called a cam deformity, which can cause pain and decreased range of motion in the hip. Cam deformities occur on the upper femur (thigh bone) and cause increased contact between the femur and the acetabulum (hip socket). Joint contact pressure is thought to play a role in accelerating the onset of OA. To determine the association between cam deformity and the onset of hip OA, Laura Given is studying how the joint mechanics change depending on the degree of cam deformity. She will track how the joint translations and rotations are affected throughout the range of motion of the hip and determine how the range of motion is affected by simulated cam deformity. By describing how the size of cam deformity affects joint mechanics, Given’s research will help surgeons understand how to effectively correct the deformity in an effort to slow or even stop the osteoarthritic disease progression. It could also lead to preliminary guidelines in arthritis screening programs. This could reduce the number of cases of hip OA seen in the future.

Preventing falls and disability in older adults after hip fracture

Every year, more than 20,000 people in Canada sustain a hip fracture. Of these, up to 20% die within 12 months and 50% do not return to their pre-fracture level of mobility. People who have a hip fracture have a higher risk of falling and an increased risk of a subsequent hip fracture compared with those of the same age who have never had a hip fracture. After a hip fracture, relative immobility initiates a vicious cycle where deteriorating balance and muscle weakness increases risk of falls and diminished bone health contributes to fracture risk. Although exercise is key to reversing this pattern, there have been relatively few clinical trials aimed at improving muscle strength, balance and enhancing bone health following hip fracture.

Dr. Maureen Ashe is conducting a randomized controlled trial to evaluate the impact of a targeted exercise program on the rate of falls, functional mobility and bone micro-architecture among older adults who have sustained a hip fracture. If successful, this intervention will result in fewer falls and improved bone health in a vulnerable senior population. Data from the research will inform recommendations for rehabilitation and contribute to the knowledge base for health-professionals, both in hospital and in the community, who manage care after hip fracture.

Measuring confidence with wheelchair mobility

In 2000/01, approximately 264 000 Canadians required a wheelchair for mobility. Independence with mobility is important for day-to-day living, social activities, and overall quality of life. However, although wheelchair skills training has become much more prevalent in the past decade, more than half of Canadians using a wheelchair are not independent and require assistance with their mobility. One factor that has not yet been explored by research is the impact of confidence on a person’s mobility and independence. Confidence contributes to the acquisition of knowledge and refinement of new abilities. It also influences an individual’s choice of activities, motivational level, effort, resilience, life choices, and perseverance in the face of difficulties. Preliminary research suggests that confidence may affect wheelchair mobility, but there is currently no tool to assess or address this important factor. Paula Rushton is developing and validating an assessment tool to measure wheelchair skills confidence. The creation of this tool involves input from occupational therapists, physical therapists and physicians, as well as wheelchair users in the community. The second phase of her project will involve testing the tool with one hundred community dwelling wheelchair users. The creation and validation of this tool is an important first step in developing treatment strategies that could address low confidence with wheelchair mobility. Ultimately, this work could result in better mobility and independence for people who use wheelchairs, and a decreased burden on the health care system and on caregivers.

Healthcare workers and antineoplastic drugs: Identifying the determinants of exposure and current challenges to reducing exposure

In health care settings, antineoplastic drugs are prepared and administered daily, mainly for the treatment of cancer. These drugs are inherently toxic and can therefore affect normal, healthy cells. On-the-job (occupational) exposure to antineoplastic drugs has been shown to cause a variety of health effects including cell mutations, adverse developmental and reproductive outcomes, and cancer. Absorption through the skin is suspected to be the main route of occupational exposure to antineoplastic drugs, and in spite of control measures used during their handling and preparation, studies have found antineoplastic drug contamination of surfaces in health care facilities. However, few studies have examined the potential for occupational dermal exposure. Chun-Yip Hon previously conducted a pilot study assessing the occupational dermal exposure risks of antineoplastic drugs to healthcare workers, and evaluated the cleaning protocols for drug-contaminated surfaces. He found that antineoplastic drug contamination of the drug preparation area is likely in British Columbian hospital pharmacies even after cleaning, and that the hands of pharmacy personnel may be contaminated even if the worker was not responsible for preparing the drug products. He’s now undertaking a full-scale study at hospitals situated within the Lower Mainland, investigating the procedures and process flows of antineoplastic drug handling, and determining who may come into contact with the drugs. He is quantifying antineoplastic drug contamination levels on surfaces throughout their process flow in each hospital, assessing workers’ knowledge of safe handling procedures as well as their risk of occupational dermal exposure. He will also determine the presence of antineoplastic drugs in health care workers through biological monitoring. Hon’s findings will determine the risk factors associated with occupational exposure to antineoplastic drugs in the health care sector, providing key information for those who work with antineoplastic drugs, occupational health and safety professionals, risk managers and policy makers.

Immunomodulation of regulatory mechanisms in mucosal immunity

Inflammatory bowel diseases (IBD) are chronic conditions characterized by severe inflammation of parts of the bowel, causing significant symptoms, such as diarrhea, pain and intestinal bleeding. There are two main types of IBD: Crohn’s disease and ulcerative colitis. IBD is prevalent in Canada, with an estimated 170,000 people suffering from the disease. Despite years of effort, the causes of these disorders remain incompletely and inadequately understood. The intestinal inflammation in IBD is thought to result from abnormal responses to the bacteria that live normally in the gut. In healthy individuals, the immune system is able to distinguish between harmless (commensal) bacteria and those that cause infections (pathogens). In IBD patients, the immune system elicits an aberrant and aggressive response against components of host commensal bacteria. Dendritic cells (DC) and regulatory T cells (nTreg) are two types of cells important in maintaining a healthy intestinal immune system. Defects in the development or function of these cells could ultimately lead to inappropriate responses to commensal bacteria, or certain commensal bacteria or pathogens could perturb the normal immune state of the gut. Dr. Gijs Hardenberg is investigating the interplay between host commensal bacteria and the immune system in IBD. He is studying the roles of nTreg and immune responses, focusing on the bacterial protein flagellin, which has been shown to be the major target of intestinal immune responses in Crohn’s disease patients. His work aims to understand how IBD begins and persists how it might ultimately be treated or even prevented. The findings from these studies may also be broadly applicable to other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and lupus.