Three Research Grants Approved for 2007 Grant Cycle

By Don Gebhart, M.D. Chair, VF Research Committee

By the September 1, 2007 deadline for research grant applications the VF had received eleven grant applications which significantly surpassed our previous number of requests for funding. The quality of the applications was excellent and the Research Committee found all of the applications met the subject criteria which have been established by the VF following the Chicago Consensus Conference of January 2006. The proposals were from the US, England, France, Italy, Spain and New Zealand and they proposed studying various different vasculitis diseases in a variety of ways.

After review by the Research Committee the study proposals were forwarded to the VF Medical Advisors for medical and scientific review. When the review was completed three study proposals stood out from the rest and these were approved for funding by the VF Board of Directors. Two grants are for one year with $50,000 to each recipient, and one is for two years with a grant of $50,000 for each year. While these studies involve three different vasculitis diseases we feel that if the goals set forth are able to be achieved they can all have a significant effect on the other vasculitic diseases. The three approved studies are listed below and include a brief description of the disease and the lay person abstract submitted by the author.

1. “An investigation of the role of the innate immune response in Kawasaki Disease” by Neil Bowles, Ph.D. from the University of Utah in Salt Lake City. This is a cooperative study with Dr. Fukiko Ichida of Japan. Kawasaki disease affects children and while it can affect many parts of the body the most debilitating involvement is the inflammation of the arteries of the heart. Kawasaki disease is a good model of a vasculitic disease in which infection in a person with genetic changes can develop the disease. This could apply to other vasculitis diseases as well. Dr. Bowles’ lay person summary follows. Kawasaki disease (KD) is a common disease in children, who experience a fever for more than 5 days, along with other symptoms, including swelling and rashes. While most children recover after treatment, up to 20% will develop problems in the blood vessels of their hearts. It is believed that KD is caused by infection with an unknown virus or bacteria. It also appears that some people are more susceptible to develop KD and heart problems. This is probably because they have changes in genes which make key proteins that protect them from bacterial or viral infections. We believe that changes in the proteins that are involved in the initial defense of the body against bacteria and viruses may cause these individuals to be at greater risk. To investigate this we propose to collect blood samples from KD patients and to isolate DNA, which is the chemical that makes up genes. We will look for changes in the DNA structure (known as the DNA or gene sequence). Initially, we will look for changes that are already known to exist in some people to see if these changes occur more frequently in KD patients than in normal people. Then we will investigate some of these genes in detail to look for changes that have not been seen before and that do not occur in normal people. If we find any changes this may mean that the protein made by this gene is important in protecting people against the virus or bacteria that causes KD. In the future, these studies may allow us to identify which individuals are more likely to develop KD, which KD patients are more likely to develop heart problems. Dr. Bowles is an Associate Professor in the Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine. He completed his undergraduate training at Queen Elizabeth College, University of London and his Ph.D. at the Charing Cross and Westminster Medical School, University of London. His Ph.D. studies involved investigations of the role of enterovirus infection of the myocardium in acquired cardiomyopathies. He then undertook postdoctoral training at the University of Geneva, Switzerland and the Baylor College of Medicine in Houston. While at Baylor he was involved in projects investigating both acquired and genetic forms of cardiomyopathies, as well as the etiologies of transplant rejection. During these studies he became interested in the role of genetic susceptibility traits to viral cardiomyopathies which lead to investigations of variations in the innate immune response. While at Baylor College of Medicine he started collaborating with Dr. Fukiko Ichida, University of Toyama, Japan who is a leading investigator of the pathogenesis of Kawasaki Disease. Upon moving to the University of Utah in 2006, Dr. Bowles initiated studies of the role of genetic variations in the innate immune response in susceptibility to Kawasaki Disease and the associated vasculitis, in collaboration with Dr. Ichida.

2. “Investigating the role of the novel Th17 cells in the pathogenesis of ANCA associated vasculitis and their potential for Immunomodulation” by Alan Salama MBBS, Ph.D. from the Imperial College of London, London, England. This study investigates the role of specialized white blood cells (Th17) which seem to play a role in inflammation and tissue damage in patients initially and with relapse that have ANCA vasculitis which includes Wegener’s granulomatosis (WG), Churg Strauss Syndrome (CSS), and Microscopic Polyangiitis (MPA). Dr. Salama’s lay person summary follows. Auto-immune diseases are those caused by the body’s own immune system. A group of these are characterized by an antibody called anti-neutrophil cytoplasmic antibody (ANCA). They cause inflammation of blood vessels (vasculitis) which result in significant health problems such as kidney failure and lung disease. Like other autoimmune diseases, they often relapse, requiring repeated treatment with drugs that suppress the immune system but have serious side-effects. In patients with frequent relapses this treatment may be required for life, while even in patients who initially respond to therapy, one in five patients with kidney involvement will go on and develop end stage kidney disease, and ultimately up to half the patients will undergo some form of disease relapse. These relapses represent a significant challenge to treatment regimens, especially for patients with Wegener’s granulomatosis or those with Proteinase 3(PR3)-ANCA in whom relapse is more common. Although we understand some of the events which perpetuate inflammation in the kidneys and lungs of patients who have disease, little is known about what initially causes it and why it relapses. Based on published evidence, it is suggested that a newly recognized, but little understood immune pathway, involving specialist white blood cells releasing a chemical called interleukin-17, might underlie both the trigger for disease initiation and relapse. In this project, we will study the role of this pathway in ANCA-related kidney disease using patients and newly established experimental model systems. As we understand more about this pathway it should be possible to specifically target these cells, treat the disease more effectively and potentially prevent the development of disease relapse. Dr. Salama is a Clinical Senior Lecturer and Honorary Consultant Nephrologist at the Imperial College Kidney and Transplant Institute, at Hammersmith Hospital. He qualified from Oxford University and The Royal London Hospital and completed his Nephrology and Internal Medicine training in London, chiefly at Guy’s and The Hammersmith Hospital. His chief clinical interests have been autoimmune glomerulonephritis, vasculitis and transplantation. He received his PhD from the Royal Postgraduate Medical School, University of London having studied the regulatory mechanisms involved in immune-mediated renal disease, specifically anti-GBM disease. Subsequently, he took up a postdoctoral NIH Nephrology training post at The Brigham and Women’s Hospital and The Children’s Hospital in Boston, USA. His research was on mechanisms of immunological tolerance in both experimental and clinical transplantation and autoimmunity. He returned to the UK to take up a Department of Health Clinician Scientist award at Imperial College, where he is now a PI investigating the pathophysiology of autoimmune vasculitis and immune tolerance as well as carrying on his clinical nephrology and vasculitis practice.

3. “Vasculitic T cells in Giant Cell Arteritis” by Cornelia Weyand, M.D. from Emory University in Atlanta, Georgia. This is a study of T lymphocytes and the underlying causes of inflammation in Giant Cell Arteritis (GCA) which affects primarily older adults and is the most common form of vasculitis. Unraveling the mechanisms of the inflammatory process could lead to new treatments for GCA, as well as, other forms of vasculitis. Dr. Weyand’s lay summary follows. Patients with giant cell arteritis/temporal arteritis (GCA) are threatened by vision loss, stroke and aortic aneurysm. Laboratory tests show intense inflammation; blood vessel biopsies reveal clusters of inflammatory cells in the walls of arteries. Such inflammatory clusters are composed of T lymphocytes and macrophages, cells of the immune system, which react to yet unknown instigators and attack vessel walls. T lymphocytes are highly sophisticated cells, equipped with a large array of receptors and the ability to release local hormone-like substances (called cytokines) to drive inflammation and tissue injury. Over the last decade T lymphocytes have emerged as key regulators causing GCA. However, little is known about how they facilitate blood vessel damage. This proposal is designed to find out how T lymphocytes communicate with other immune cells and cells of the arterial wall to promote disease. The experiments are made possible because we have generated two experimental models in which we can study blood vessel wall inflammation: we engraft human arteries into mice or we generate human arteries through bioengineering. First, we will examine whether vasculitis is caused by T lymphocytes specialized in producing IL-17, a cytokine recently implicated in driving autoimmune disease. We will then explore whether T lymphocytes in GCA patients can kill essential cells, in particular vascular smooth muscle cells that form the scaffold of the blood vessel. We already have preliminary data that such killer T cells are circulating in the blood of GCA patients. Finally, we will use state-of-the-art techniques to discover new pathways through which lymphocytes damage the blood vessel structure. These experiments involve gene expression profiling and sophisticated bioinformatics methods to identify pathways of interest. The ultimate goal is to overcome our current limitations in treating GCA by opening new avenues for novel therapeutic and diagnostic approaches urgently needed for affected patients. Dr. Weyand is a Professor of Medicine and Co-Director of the Lowance Center for Human Immunology. She received her training at the University of Aachen, Germany, the University of Heidelberg, Germany and the Mayo Graduate School, Rochester, Minnesota. She is one of the world’s leading experts on giant cell arteritis.