University of California, San Diego

Kelly Award Recipient

The role of Interleukin-18 in the autoinflammatory disease spectrum, the cryopyrin-associated periodic syndromes

The innate immune system acts as a first line of defense against invading disease-causing organisms (such as bacterium or viruses), revving up the immune response so the adaptive immune system can be tailored to prevent re-infection with the same organism. No longer just considered a stop-gap measure, the innate system communicates with the adaptive system through various cells and cytokines, long after the specific response is established.

Dr. Brydges is studying “CAPS”, (inherited cryopyrin-associated periodic syndromes) caused by mutations in a protein called cryopyrin. This mutation causes an inflammatory response in the body even when no infection is present. Starting at birth, CAPS patients have unprovoked fevers, rash, and arthritis resulting from unregulated production of these pro-inflammatory molecules. Dr. Brydges designed a cryopyrin mutant mouse model which she is using to determine the role of the pro-inflammatory cytokine, IL-18 in CAPS.

Although CAPS is rare, its primary outcomes, overproduction of IL-1B and IL-18 (pro-inflammatory cytokines) and their downstream effects, are nevertheless relevant to common forms of arthritis. Since spontaneous inflammation begins early in life, CAPS may also be relevant to understanding the initiating events of juvenile idiopathic arthritis (JIA). JIA is so complex that it is difficult to elucidate specific pathways or develop targeted therapies. Dr. Brydges therefore hopes the simple mouse model of CAPS will provide a better understanding of the innate immune system and its role in the larger picture of immunity as a whole.

University of Virginia School of Medicine

Josephine Rich Memorial Fellow

New strategies for treatment of osteonecrosis using stem cells and growth factors

Osteonecrosis, also known as bone death, is a devastating disease affecting young patients at their most productive age. It involves major weight bearing joints, especially hips and knees, leading to severe arthritis causing pain and disability. The pathogenesis is unknown and there is no effective prevention and treatment. The purpose of this study is to determine new strategies for treatment of bone death and to find out why bones die in this disease.

Dr. Cui will study bone marrow stem cells that carry growth factors, which help to grow vessels and bones, to see if they will enhance the regeneration of new bone in dead bone. In this study, bone marrow stem cells will be manipulated so they can carry growth factors and will be used to treat bone death in an established bipedal chicken model. Successful completion of the project will advance our understanding and knowledge of growth factors, their role in tissue engineering and the association between vessel and bone regeneration in dead bone.

St. Louis University

John Vaughan Scholar

Adoptively Transferring GPI-specific Regulatory T cells to treat the Effector Phase of Rheumatoid Arthritis

The immune system generates a population of cells known as regulatory T cells. These cells are the immune system’s way of controlling inflammation and preventing the development of various autoimmune diseases. Many scientists are studying regulatory T cells to learn how to use these cells to treat inflammation and autoimmunity. If regulatory T cells are to be of clinical use, they must be able to suppress inflammation when administered during later stages of an ongoing autoimmune disease.

Dr. DiPaolo has discovered that regulatory T cells can be used to reduce the severity of inflammation and joint disease in a mouse model of Rheumatoid Arthritis (RA). In this project, Dr. DiPaolo will determine how effective this treatment is at more advanced stages of disease. In addition he will investigate cellular targets and mechanisms used by regulatory T cells to suppress inflammation in the joints. These studies will provide novel insight into the potential to use regulatory T cells, or drugs that mimic their activity, to treat RA and potentially other autoimmune diseases.

NYU School of Medicine

Don H. Minassian Memorial Fellow

18Fluorodeoxyglucose PET and MRI Assessment of Atherosclerotic Plaque and the Effects of Anti-TNF Therapy in Rheumatoid Arthritis Patients

Cardiovascular (CV) disease is a major medical problem and cause of mortality in patients with rheumatoid arthritis (RA). Evidence suggests that inflammation associated with RA may play a major role in the development of CV disease. Novel non-invasive imaging techniques, including magnetic resonance imaging [MRI] and 18fluorodeoxyglucose positron emission tomography scan [FDG-PET/CT]), have been developed to characterize the atherosclerotic plaque and associated inflammation in the blood vessel wall.

In this study, Dr. Greenberg will use MRI and FDG-PET/CT to determine whether anti-TNF therapies can improve vessel wall inflammation and plaque characteristics in RA patients. Patients will undergo FDG-PET/CT and MRI of the carotid arteries and the aorta. FDG-PET/CT and MRI outcomes will be compared at baseline versus 6 months after initiation of anti-TNF drugs. Dr. Greenberg hypothesizes that vessel wall inflammation and plaque burden will be attenuated with anti-TNF therapies. The results of this study will contribute to knowledge of potential risk reduction strategies for CV disease in patients with RA.

Oklahoma Medical Research Foundation

Melba M. O’Connell Memorial Fellow

Biomechanical Stimulation of Cartilage Antioxidant Function

As the primary cause of disability among older Americans, treating and preventing osteoarthritis represents a major opportunity for extending the healthy life spans. Altered loading of joints, as occurs with obesity or joint injury, is considered a primary risk factor for osteoarthritis. However, some forms of increased loading, such as physical therapy and exercise, reduce joint pain and improve function. It is not well understood how some forms of joint loading cause damage while others are protective.

Different types of joint loading may protect, or damage, the joint by altering the production and clearance of free radicals. Free radicals are highly reactive molecules capable of causing oxidative damage to DNA, proteins, and lipids. Osteoarthritis is associated with increased levels of oxidative stress and damage in joint tissues. Dr. Griffin is testing the idea that normal types of joint loading, such as those from exercise, help protect cartilage from oxidative damage by increasing the intrinsic antioxidant function of the tissue. In addition, he is studying how the level of loads applied to cartilage affects the ability of cartilage to get rid of damaging free radicals and pro-oxidants. The ability of cartilage to remove excess levels of free radicals may be critical for maintaining joint health with aging.

By better understanding the ways in which biomechanical stimulation alters free radical production and removal, we hope to identify new therapeutic approaches for treating osteoarthritis, particularly in the context of joint injury, obesity, and aging. Furthermore, this research may lead to new strategies for Tissue Engineering applications whereby biomechanical preconditioning may improve implant survival and function by upregulating cellular metabolic and antioxidant pathways.

The Scripps Research Institute

Jack and Vonnie Schlomer Memorial Fellow

The role of cartilage specific miRNA in osteoarthritis pathogenesis

Osteoarthritis (OA), the most prevalent age-related joint disease, is characterized by degradation in joint cartilage. Molecular mechanisms that govern the development and maintenance of cartilage are currently being characterized and this has the potential to lead to new therapies. Small, non-coding microRNAs (miRNAs) are new negative regulators of gene expression and have been associated with disease such as cancer and heart disease, as well as arthritis; however, their role in cartilage maintenance and repair is largely uncharacterized.

In Dr. Miyaki’s research, miRNAs are novel regulators of cartilage growth and development. Changes in miRNA expression and function play an important role in OA pathogenesis.

The proposed studies have the potential to reveal important new regulatory pathways that control cartilage growth and open new insight to OA mechanisms. Dr. Miyaki will try to identify novel tools and targets for arthritis using this strategy.

University of Colorado, Denver

Beverly Howland Memorial Fellow

The role of Arginase 1 in alphavirus-induced arthritis, tenosynovitis, and myositis

An estimated 46 million people in the United States suffer from rheumatic diseases. These diseases are caused by combinations of a variety of genetic and environmental factors, including some viruses and other microbes. Although rheumatic diseases have different causes, they can all lead to painful and sometimes incapacitating inflammation of joints, muscles, and bones. In order to develop new treatment strategies, we need to learn how inflammation causes the symptoms of rheumatic diseases.

Chikungunya virus and Ross River virus are transmitted to humans by infected mosquitoes and cause fever and painful inflammation of joints, bones, and muscles that may last for months to years. These viruses can cause large epidemics of rheumatic disease and spread to new regions of the world. Dr. Morrison’s lab has developed novel mouse models to study the inflammatory disease caused by these viruses and he will use these models to learn how inflammation leads to damage of joints, muscles, and bones. In addition, these models will be used to test drugs that may treat these painful symptoms.

An important component in inflammation is the activation of cells of the immune system called macrophages. While certain types of activated macrophages may be good for some diseases, other types of activated macrophages can be harmful. Dr. Morrison will study how specific functions of macrophages are regulated during inflammation and how macrophage activation contributes to inflammatory arthritis. Because macrophages play a central role in inflammation, this research on virus-induced arthritis may lead to new ways to treat a wide range of human rheumatic diseases.

University of Arizona

Frances D. Morongo Memorial Fellow

Characterization of pathogenic Th17 responses in collagen induced arthritis

Recent research in immunology has shown the integral role of a particular type of immune cell in mediating autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis. This cell is called the Th17 cell, as it secretes the molecule IL-17. IL-17 protects the body from infections and can also mediate inflammation of target tissues often seen with autoimmune diseases.

The Th17 cell can also secrete other molecules besides IL-17. With the support of ANRF funding last year, Dr. Sarkar has identified other molecules that are produced by the Th17 cell in the context of inflammatory arthritis, all of which have the potential of augmenting joint inflammation. She is currently identifying functional characteristics of the Th17 cell.

With the second year of funding from ANRF, Dr. Sarkar will be identifying the triggers within the immune system that lead to the generation and maintenance of the Th17 cell during inflammatory arthritis. The findings from the proposed studies will identify new targets in inflammatory arthritis pertaining to the Th17 pathway and will also lay the foundation for comparing the characteristics of this response to other Th17 associated diseases, such as psoriasis.

Brown Medical School/Rhode Island Hospital

Grace Haussner Memorial Fellow

Inducible deletion of Ihh Prevents Osteoarthritic Cartilage Degeneration

Osteoarthritis affects over 27 million people in the United States but the pathogenesis of OA remains under active investigation. Recent evidence suggests that a bioactive protein within the joint called Indian hedgehog (Ihh) is involved. The study will provide insight into the mechanism of cartilage degeneration mediated by Ihh, and important data regarding the potential efficacy of Ihh-targeted therapies for treating osteoarthritis.

UCLA

James Klinenberg Scholar

Programmed death-1-Programmed death-1 ligand (PD-1-PDL-1) pathway in the New Zealand Black x New Zealand white murine model: a molecular approach

Maida Wong, M.D., has a personal vendetta against lupus. When she was in medical school, her father was diagnosed with lupus and died shortly thereafter. Her passion to discover a cure for lupus is personal.

Dr. Wong’s research will study the molecular pathway of lupus using a mouse model. Studies have shown that mutation in the gene responsible for this particular pathway results in increased susceptibility to systemic lupus erythematosus (SLE or lupus) in humans and in mice. Dr. Wong is continuing her work manipulating the programmed death-1 (PD-1) gene, testing to see if PD-1 regulation could represent a target to preserve immune tolerance and prevent autoimmunity in lupus.