Jonathan Choy – The role of IL-17 receptor A in transplant rejection
Organ transplantation is the only treatment for end-stage organ failure. As such, it is a potentially curative procedure for devastating conditions such as kidney, heart and liver disease. The success of organ transplantation is limited by the rejection of grafts by the immune system of recipients. Activation of the immune response that causes rejection depends on the actions of proteins that signal between cells, termed cytokines. IL-17 is a cytokine that has been implicated in transplant rejection but little is known about how it does this. Also, one of the main types of rejection that is particularly difficult to manage is caused by the production of antibodies that target transplanted organs. Dr. Choy’s laboratory has preliminary evidence that IL-17 may contribute to immune-mediated rejection of transplanted organs by supporting the development of antibodies that target the graft. The proposed studies will examine how IL-17 contributes to transplant rejection through supporting the production of antibodies. The findings have the potential to identify new therapeutic targets for the prevention of organ transplant rejection.
Tom Blydt-Hansen – Investigating serum immunometabolomic profiles associated with kidney transplant alloimmune outcomes
Transplantation is the leading treatment for people with end-stage kidney failure. But beyond the first year after transplant, we know some people will develop chronic forms of rejection that limits the transplant survival. We know that some people’s immune systems adapt better or become more “tolerant” to the transplant, but we don’t know all of the reasons why. While medications are an important part, we also know a person’s metabolism can play a role. That includes things like nutrition and disease, which can influence how a person’s immune system will respond. Under the right conditions, the immune system may be more likely to “adapt” to the transplant and avoid chronic rejection.
This study will look at samples that have been collected before transplant, to see if there are changes we can measure in metabolism that predict who will have a positive (tolerant) or negative (rejection) response to the transplant. We will use blood samples collected from people before transplant and test for hundreds of small molecules (called metabolites). We will look for patterns of these metabolites that might predict who is more likely to develop chronic rejection and also early rejection. We will use this information to develop a test that could be used before transplant to tell people about their risk of rejection. It may also help to identify why that risk is higher, and ways to reduce the risk.
We hope that this research will help us understand and predict who is at high-risk for chronic rejection, and give us clues about how we can change them before transplant to improve chances for long-term transplant survival.
Kathryn Armstrong – “Lets Talk Teenage Transplant”: Using Text Messaging to Engage with Adolescent Solid Organ Transplant Patients
Adolescence is a crucial time in the transplant journey. During this time patients experiment with not taking their medications and are resistant to attending medical appointments. Choosing not to take medications or follow medical advice can have significant consequences and can lead to serious and life-threatening illness. The reasons for these choices are not well understood and likely depend on several factors, but may be partly attributed to the ongoing development of executive function which occurs throughout adolescence. Executive function (EF) refers to a set of skills that are required to plan and perform complex tasks.
Establishing better communication between adolescents and their health care providers (HCP) may help adolescents gain the skills to plan and perform complex tasks related to their health (ie. taking medications or filling a prescription). This fosters independence and teaches the adolescent how to manage their own health. Currently, parents are the primary communicators with HCP. Improved communication methods between HCP and adolescent patients are needed. Text messaging is a preferred way for adolescents to communicate. Due to hospital policies, HCP are unable to text message their patients. Using a short messaging service (SMS) platform allows for communication via text messaging in accordance with hospital policies. The goal of this project is to implement a SMS platform to communicate with adolescent transplant patients and to determine its effect on health outcomes.
Caren Rose – Examining the Impact of overdose deaths on solid organ transplantation
Canada is facing a worsening opioid overdose crisis. This has resulted in a dramatic increase in the number of overdose related deaths, now surpassing all other causes of unnatural deaths. On average four people die every day in BC as a result of overdose; the majority of these are relatively young adults (aged 18-50). In parallel, the number of people dying as a result of organ failure is increasing. Many of these patient’s lives can be saved or improved with organ transplantation. Unfortunately, the number of organs available for transplantation is too small to help all people who could benefit. People dying from opioid overdose can become organ donors. In fact, 25% of transplantation in BC is currently a result of organ donation from people dying of overdose. However, when someone dies of overdose there is concern that they are at higher risk of having viruses such as HIV and Hepatitis B and C, and that they may transmit these viruses to organ failure patients via transplantation. This theoretical concern may lead to non-utilization of these potential donors or their organs for transplantation, despite the otherwise good health of organs from these donors. This project will determine the safety of organ transplantation from overdose donors (i.e. disease transmission and survival), and examine patterns of non-utilization of donors and their organs.
Mercedeh Kiaii – The Impact of Slow Efficiency Hemodialysis on the Duration of Delayed Graft Function: A Feasibility Pilot
Kidney transplantation is the preferred treatment for patients with kidney failure. Unfortunately, the number of kidneys available for transplantation is insufficient to the meet the need for transplantation and patients wait up to eight years to receive a transplant from a deceased donor. To help meet this need, it is necessary to use kidneys from older deceased donors and other donors at risk for post transplant complications. These kidneys can be successfully transplanted but are at increased risk of complications after transplantation that can compromise transplant survival and success. One of the most important complications is failure of the kidney to immediately function after transplantation known as delayed graft function (DGF). During DGF patients must be supported by dialysis, which itself can prolong the duration DGF by causing low blood pressure and increasing inflammation. Remarkably no studies have addressed the optimal way to provide dialysis in patients with DGF. We hypothesize that long intermittent dialysis, which minimizes the adverse effects of dialysis, will reduce the duration of DGF compared to conventional dialysis treatment. The proposed study will inform the feasibility of a definitive randomized controlled trial to determine whether long intermittent dialysis will reduce the duration of DGF leading to better short and long term transplant outcomes.
Dr. David Granville
Granzyme K in Allograft Vasculopathy and Expression in Cardiac Tissue
Heart Failure is a common disease affecting at least 23 million people world-wide and its occurrence is increasing given that more people are surviving heart diseases. 1 in 5 people over 40yrs are predicted to develop heart failure with a death rate of 50-60% over 5 years. Heart transplantation is the gold-standard treatment in patients with end stage heart failure. Transplant rejection is the major limiting factor in long term survival of transplant patients. There are 2 types of immune rejection; early (acute) and late (chronic). Late rejection is dominated by immune damage to the blood vessels that feed the transplanted heart. As a result, scar tissue narrows these blood vessels and the heart muscle is deprived of oxygen and nutrients and the heart ultimately fails.
Immune cell infiltration is one of the earliest steps in late rejection. Immune cells can cause damage to the transplanted heart by secreting protein-degrading enzymes known as Granzymes. These so-called proteases damage the inner layer of the blood vessels of the transplanted heart causing them to die.
Granzyme K (GzmK) has been shown to be highly elevated in patients with late rejection and causes significant inflammation in blood vessels. Using a mouse model of human transplant rejection and mice that genetically lack GzmK, we will test whether GzmK deficiency results in reduced late rejection and inflammation. This project will provide key proof of concept data as to whether to pursue GzmK as a future drug target for attenuating chronic transplant rejection. Ultimately our goal is to reduce the impact of late rejection and increase transplant patient survival.
Dr. John Boyd & Dr. Mark Kearns
The Donor Heart After Withdrawal of Life Support
The biggest problem in heart transplantation is the shortage of donor hearts. This shortage results in the death of significant numbers of patients with end-stage heart failure who would have been eligible to receive a new heart. To boost the number of hearts available for transplantation, researchers have been investigating alternative pathways for heart donation. One solution that has significantly increased the number of organs available for lung, liver, and kidney transplantation is referred to as donation after circulatory death (DCD). The biggest problem with DCD hearts is that they are injured because of the donation process and we still can’t precisely identify which heart would be safe or unsafe for recipients. Addressing this problem would remove a major barrier to the use of DCD hearts for transplantation, and reduce the number of people dying unnecessarily on transplant waiting lists.
The main objective of this proposal is to study human DCD hearts on a machine, to find ways of identifying when a heart is too injured, and therefore unsafe to use for a recipient. This approach would allow surgeons to make decisions about a heart’s suitability before committing a recipient to a heart with an uncertain outcome. In most of the world (including British Columbia), DCD hearts are not currently used for transplantation. In fact, these hearts are simply discarded. This represents a lost opportunity for researchers who could put the heart to good use, and make valuable discoveries that would benefit heart failure patients and society.
Dr. Tom Blydt-Hansen
Quality of life and mental health needs of children after solid organ transplantation in BC
Severe kidney, hear or liver failure that is life threatening can be rescued by organ transplantation. Children and families who have survived these critical illnesses often carry mental scars related to their experiences with organ failure. They have endured testing and treatment in times of intense vulnerability, as well as dependence on life-support technologies, operations, and critical illness that may require extended hospitalization. As a result, children and their parents experience intense and chronic stress, isolation, family disruption and restriction in their ability to participate in “normal” childhood activities. The long-term impact of these experiences is not well understood in children and needs further study.
We expect that children with this lived experience may suffer symptoms related to anxiety, post-traumatic stress, depression and impaired tolerance of medical procedures. It may affect their social and emotional development, interfere with their peer relationships and prevent them from attaining a quality of life equivalent to their peers. Quality of life is perhaps the most important outcome for solid organ transplant recipients, given that the goal of transplantation is rehabilitation with restoration of organ function.
We have previously initiated mental health and quality of life screening in the transplant clinic at BC Children’s Hospital. The gaol was to understand the needs and improve access of children and families to mental health services. We learned quickly that the need is great. This research proposal will review the results from screening to learn what types of mental health symptoms are most common, their severity and to understand how they impact quality of life. We will also review the medical history of children before transplantation to see if there are early warning signs that might help us to identify children and families who are at risk of mental health distress much earlier, and before transplantation. With this information, we will be able to better get mental health services to children and families earlier and support them better through this difficult time. We will also use this information to raise awareness and obtain better access and funding for mental health resources to support this vulnerable population. Ultimately, we hope to develop better interventions that holistically enhance rehabilitation of children after transplantation and improve their long-term quality of life.
Dr. Kevin Harris
Early detection of artery thickening in pediatric heart transplant recipients
Children who have had a heart transplant are at risk for developing a disease called cardiac allograft vasculopathy (CAV) where their coronary artery walls thicken over time. Sadly, CAV is responsible for 1 in 4 patient deaths. The current way to look for CAV is to use a technique called angiography where dye is injected directly into the coronary arteries and imaged. However, the limitation of angiography is that it can only detect late stage disease and therefore treatment is less likely to work. For this project, Dr. Harris will use a new imaging technique called optical coherence tomograph (OCT) to detect problems developing in children’s heart transplant grafts early enough to treat the problem. OCT is an imaging technique designed for use in adults that is beginning to be used in children. Dr. Harris has already performed a preliminary OCT study and found that OCT detects artery thickening earlier than angiography in children heart transplant recipients. He will now use OCT to follow these children over time in order to establish this technique for reliable, routine use.
Dr. Amee Manges
Treating multi-drug resistant infections in Transplant recipients with fecal microbiota transplants
Organ transplant patients are at increased risk of developing highly antibiotic resistant infections as a result of their transplant surgery, lengthy hospitalization and repeated use of antibiotics during their medical care. The source of these multidrug-resistant bacteria is the patient’s own gut. In this study, Dr. Manges will test whether fecal microbiota transplantation (FMT) can remove highly drug-resistant bacteria from the gut of kidney transplant patients. FMT is a therapy that involves the infusion by enema of well screened, healthy donor stool into a patient’s gut. FMT can replace the gut microbial community containing these drug-resistant bacteria, with a microbial community characterized by more beneficial organisms with lower levels of antibiotic resistance, thereby lowering a kidney transplant patients risk of hard to treat, post-transplant infections. The goals of this study are to confirm that FMT can eliminate drug resistant bacteria from the gut of Transplant recipients, and to determine how long the patient remains free of these drug resistant organisms.
Dr. Sam Wiseman
Transplantation of thyroids enclosed in protective pouches
The thyroid gland makes hormones which control how quickly the body uses energy, makes protein and controls the body’s sensitivity to other hormone. The thyroid is often removed because of cancer or benign disease (several hundred thousand per year in N America), and loss of thyroid function leads to severe illness and disease so these people take thyroid hormone (thyroxine) replacement therapy. But people receiving thyroxine still experience side effects (weight gain, depression, headaches, cardiovascular disease) because taking thyroxine is not the same as having a functional thyroid gland that can monitor the body’s metabolism and produce hormones in real time as it is needed. Transplantation of thyroid gland back into these people would give better metabolic control. Dr. Wiseman will test whether thyroid glands obtained from deceased donors can be placed inside a special pouch and implanted into a recipient. The pouch will protect the thyroid gland from attack by the immune system so the recipient can live a normal life with a functioning thyroid gland without having to take anti-rejection drugs.
Eliminating barriers to organ donation registration
Dr. John Gill
Integrating registration for organ donation into routine health care encounters
Canadians have made it overwhelmingly clear they support organ donation, yet this does not translate into eventual donation. Our deceased organ donor rate is around 15 per million people. This ranks us 23rd in the world behind countries such as Croatia, Puerto Rico and Latvia. Dr. John Gill is a renowned researcher in the field of kidney transplantation and a respected nephrologist. He is also an advocate for increasing organ donation. Dr. Gill and his team propose eliminating one potential barrier by getting health care providers to discuss organ donation with patients during routine health encounters. His project will establish protocols and quantify their effect on the rate of organ donation. By “normalizing” the conversation around organ donation, much as the medical system in BC has done with routine HIV testing, Dr. Gill believes we can greatly enhance organ donation rates.
A new source for kidneys?
Dr. Chris Nguan
Development of Multi Allograft Kidney Organ (MAKO) units from nephrectomy specimens for meeting kidney transplant donor supply
With kidney transplant waitlists in BC up to ten years long, one of the province’s leading urologic surgeons is hoping to find a potential new source of kidneys. Dr. Chris Nguan’s primary clinical focus is renal transplantation but he has a keen interest in advanced technologies research. He believes a potential new source of kidneys could be those that are removed for reasons such as kidney stones, obstruction and small tumors. Even though only part of the kidney is damaged, the entire organ is usually discarded. Initial research has shown some of these discarded kidneys can be successfully repaired and transplanted. Dr. Nguan and his team want to go one step further by taking smaller portions of disease-free discarded kidneys and devise surgical techniques to reassemble them into a whole functioning organ. These reassembled kidneys can then be used for transplantation.
Dr. Caigon Du
A novel flush/preservation solution for cold preservation of donor organs for transplantation
Cold preservation of donor organs is a crucial aspect of organ transplantation, not only to keep the organ viable but also to prevent as much cellular damage as possible during the time the organ is out of the body. Several organ-preservation solutions are available, but they are not satisfactory and as a result organ damage still occurs. Thus, a new cold storage solution that can prevent cellular edema and tissue destruction is needed for the safe preservation of donor organs before they are transplanted into recipients. We have developed a novel cold storage solution that has the potential to minimize cold ischemia-related injuries in donor organs. Preliminary studies have demonstrated our novel polymer-based solution significantly increased cell survival of cultured human endothelial cells at 4oC, and reduced tissue damage of murine hearts during cold storage. However, more preclinical studies are needed to prove our hypothesis and test the efficacy in animal models. In this proposal, we would like to further evaluate the beneficial effect of this polymer-based solution on cold organ preservation using transplantation models.
Dr. Jan Dutz
Use of Topical Immunosuppressive Drugs for the Induction of Tolerance to Allogeneic Skin Transplantation
Solid organ transplantation may be a life-saving treatment in individuals with illnesses that have caused organ failure. However, a challenge remains in preventing graft rejection and eventual graft loss. Organ rejection is caused by the patient’s white blood cells recognizing the donor organ as foreign (hence dangerous) and mounts an immune response to attack the organ. Current strategies to minimize organ rejection include matching recipients with donors according to their genes and by controlling the patient’s immune system with immunosuppressive drugs. Although current immunosuppressive drug therapy has dramatically improved early transplant outcomes, the long-term rate of organ rejection has not decreased substantially and the use of immunosuppressive drugs can induce serious side effects. Therefore, we need a better method of educating the immune system to tolerate a foreign organ. We think that expanding the number of regulatory T cells in transplant patients will help them accept the foreign organ, minimizing the need for life-long immunosuppressive drug therapy. Corticosteroids and Vitamin D are two immunosuppressive drugs that can direct our bodies to make regulatory T cells. Our laboratory has shown that topical application (rubbing onto the skin) of Vitamin D and corticosteroids generates regulatory T cells, and it is less toxic than the traditional oral method of delivering the drugs. We would like to optimize the method of drug delivery through the skin to make regulatory T cells and evaluate its efficacy to prevent organ rejection in laboratory animals. This delivery method is less toxic than administering the same kind of drug orally. In addition, it should prevent long- term side effects in patients: the cream is applied only for a short period before and after transplant, whereas the oral drug must be taken for the rest of a patient’s life.
A Novel Tolerance Induction Strategy for Allotransplantation
Within the immune system, there is a subgroup of immune cells, called T-regulatory cells. The function of these cells is to control and regulate other immune cells and prevent destruction of transplanted organs. One very promising solution to the problem of rejection is to generate tolerance. This can be done by increasing the number of this special T regulatory immune cells in transplant recipients’ bodies. In our BC Venture Grant, we proposed to find a novel and effective way to protect transplanted organ without putting the patients’ health in danger by avoiding the use immune suppressing medications.
Use naturally immune privileged cells in islet transplantation
Parts of hair follicles exhibit “immune privilege” due to the secretion of immuno-regulatory factors and a lack of expression of the human leukocyte antigen (HLA proteins) on their cell surface. It is the HLA antigens that are recognized by the immune system and lead to organ transplant rejection. Because these unusual hair follicle cells do not have HLA antigens on their surface, they are not “seen” by the immune system. Unlike most cells and organs, the hair follicle cells are not rejected when transplanted from one person to another. These hair follicle cells also actively secrete factors that suppress local immune system activity. We propose to use these cells, with their natural non- or low-immunity, to locally protect transplanted islets. We will “coat” islets with the hair follicle cells to provide a protective shield for the islets against rejection by the transplant recipient’s immune system. After transplantation, the hair follicle cells will hide the islet cells from the immune system but allow them to function and control blood sugar levels. If this approach is successful, it will provide a simple way to transplant islets to people who have type I diabetes. It should be a permanent treatment that will avoid the need for using immunosuppressive drugs and will mean that diabetic patients no longer need use insulin injections to control their blood sugar levels.
Dr. Bruce McManus
McManus Clinical Implementation of Diagnostic Biomarker Assays in Heart and Kidney Transplantation (BiT3)
Dr. Olwyn Johnston
Quality of Life After Living Kidney Donation: No-directed Versus Directed Donor
There has been an expansion of living kidney donation in Canada with the National Living Donor Kidney Exchange Program. However the quality of life after non-directed living kidney donation (paired exchange or anonymous kidney donation) is not well established. We hypothesize that quality of life after non-directed is equivalent to that after directed living kidney donation. We anticipate that there will be no quality of life differences between directed and non-directed giving additional evidence to support further expansion of non-directed living kidney donation which in turn would potentially reduce the prolonged waiting time for deceased donor kidney transplantation in British Columbia.
Dr. David Granville
Granzymes in allograft vacsulopathy
We have detected an increase in enzymes in patients experiencing chronic rejection following heart transplantation. We propose to investigate the consequences of these increased enzymes in the context of inflammation and wound repair. We hypothesize that increased enzymes lead to impaired wound healing.
Dr. Megan Levings
Tailoring Tregs: A Novel Approach to Generate Alloantigen Specific T Cells
We are studying how a type of white blood cell, known as a T regulatory cell, or Treg, can be used as a new way to control how the patient’s immune system responds to a foreign organ. We think that by increasing the numbers of Tregs in transplanted patients will be a new way to prevent organ rejection that will not come with the side effects of the immunosuppressive drugs that are currently used. In this proposal we aim to develop a new way to make Tregs that will specifically control immunity to transplanted organs without impacting any other aspects of the patient’s immune system. If successful, this approach would represent a major step towards implementing the use of Tregs as a novel cell-based therapy to improve the long-term success of organ transplantation.
Dr. David Granville
Granzymes in allograft vasculopathy
Dr. Jonathan Choy
Role of Bim in heart transplant rejection
Dr. Julian Christians
Identification of novel targets for intervention in Aspergillus infections