Stanford University

Jack and Vonnie Schlomer Memorial Fellow
New humanized mouse model of chronic rheumatoid arthritis in humans

In rheumatoid arthritis (RA), the immune system attacks and damages the individual’s own joints. RA is characterized by episodes of acute inflammation, followed by long periods of smoldering disease with chronic joint pain and slow but progressive cartilage and bone destruction, eventually leading to loss of joint function. Recently, significant progress has been made in understanding the underlying causes of RA. The cytokine IL-17 has been implicated in the pathogenesis of RA, particularly with respect to bone erosions. Furthermore, a subtype of T cells (Th17 cells) has been found to produce abundant amounts of IL-17. These observations make IL-17 an exciting new target for the treatment of severe RA.

During the past year Dr. Cham has demonstrated that her humanized mouse model of RA develops a very severe arthritic disease which persists even after the acute phase of inflammation has subsided. By using imaging tools, areas of inflammation could be seen specifically in the paws of arthritic mice. In the coming year, she plans to use the humanized mouse model of RA to test a potential biological therapeutic, anti-IL-17. She will compare the efficacy of anti-IL-17 treatment with anti-TNF therapy (a well-tested therapy for RA) by evaluating the following: 1) how well anti-IL-17 controls inflammation in established disease and 2) whether anti-IL-17 blocks destructive bone erosions seen in the later stages of disease.

Brigham and Women’s Hospital

Frances D. Morongo Memorial Fellow
The mechanisms of LTB4-induced migration and invasion in fibroblast-like synoviocytes (FLS)

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that primarily targets synovial tissues, which forms the joint lining and produces lubricating and cushioning synovial fluid. It is relatively common with a prevalence of approximately 1% in adults worldwide.
To create new therapies to fight this inflammation, the mechanisms causing inflammation must be understood. Fibroblast-like synoviocytes (FLS), the major cellular populations in the synovial lining, directly contribute to inflammatory arthritis through aggressive invasion into the cartilage and bone. Dr. Chen’s lab has demonstrated a critical role of leukotriene B4 (LTB4), an inflammatory mediator, in inflammatory arthritic mouse models. Dr. Chen’s project seeks to understand the role of LTB4 in synovial inflammation in the pathogenesis of inflammatory arthritis.
Defining these mechanisms in the mouse will permit focused exploration of similar mechanisms in humans. Ultimately, such work may eventually provide new therapeutic options for patients with rheumatoid arthritis.

St. Louis University

Don H. Minassian Memorial Fellow
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.

Dr. Di Paolo will examine whether regulatory T cells can be used to reduce inflammation and disease in a mouse model of rheumatoid arthritis (RA). He has shown that these cells can prevent the development of RA when given before the disease process has begun. In this project, Dr. Di Paolo will investigate whether these T cells can be used as an effective treatment when given after the disease is already in progress. He will also investigate the mechanism(s) used by regulatory T cells to suppress inflammation in the joints. These studies will provide valuable insight into the potential to use regulatory T cells, or drugs that mimic their activity, to treat RA and potentially other autoimmune diseases.

Oklahoma Medical Research Foundation

Genes for early systemic lupus erythematosus autoimmunity in African Americans

Systemic lupus erythematosus (SLE or lupus) is a complex disease with a variety of clinical manifestations, many of which can be debilitating or even fatal. It affects African Americans more frequently and more severely than other races in the U.S. It is known that genes play an important role in both whether a person gets lupus and how severely they will be affected. It is also known that the environment plays a role as well. Recent studies have isolated some chemicals in the blood, called antigenic epitopes that are only found in lupus patients and almost always precede a diagnosis of lupus.

Thanks to many willing African American participants, both with and without lupus, Dr. Gray-McGuire will seek to find the genes that cause the production of these chemicals and then explain how their production leads to lupus. She will conduct this project using new biotechnology and computational tools that allows them to scan the human genome with great precision. Upon the successful completion of this project, Dr. Gray-McGuire believes we will be one step closer to detecting lupus before it begins its destructive course.

Stanford University

Ethelmae Haldan Grant for Innovative Research in Osteoarthritis
Multi-factor knee meniscus tissue engineering

Osteoarthritis (OA) is the most common type of arthritis, and is often viewed as age-related, “wear and tear” degeneration of the cartilage lining the joints. OA of the knee is one of the most prevalent causes of adult pain and physical disability. The knee meniscus is a type of cartilage which cushions the knee joint. Injuries to the meniscus, which occur fairly frequently, have been shown to accelerate osteoarthritic degeneration, and current treatment options for repair do not stop degeneration. Creating the meniscus in the laboratory via tissue engineering could potentially create a supply for repair and/or replacement tissue, that is, if a viable cell source can be established.

Dr. Lam’s work will manipulate adult stem cells taken from liposuctioned fat to become meniscal-like cells. Due to the fact the knee is a highly mechanical environment, Dr. Lam wll apply mechanical forces combined with various biochemicals to encourage the cells to becme more like meniscus cells. These cells will then be used to engineer a meniscus replacement.

Results of the work will provide valuable insight into the cellular response of adult stem cells to mechanical environments and provide tools for encouraging stem cells to become specific cell types. Ultimately, Dr. Lam hopes that she will create a readily available source of transplant tissue for future patient treatment.

UCLA

Josephine Rich Memorial Fellow
The Influence of Leptin on Regulatory T cells in Murine Lupus

The immune system is made of tissues and cells that have the task to protect against disease-causing pathogens or tumors. To function properly, the immune system needs to discriminate between foreign agents and the body’s own cells. When this process does not function properly and the immune system attacks self tissues as if they were foreign, autoimmune disease ensues. This is the case of systemic lupus erythematosus (SLE or lupus), an autoimmune disease that affects various tissues and organs including the kidneys, lungs, heart and brain. Lupus is a disease more common in women than in men, and both genetic and environmental factors are implicated in its pathogenesis.

Regulatory T cells have an important role in preventing autoimmune disease, and are numerically and functionally reduced in lupus. It was recently shown that the activity of the regulatory T cells can be negatively controlled (at least in part) by leptin, a hormone that not only regulates metabolism but also plays an important role in the pathogenesis of several autoimmune diseases.

In this project, Dr. Lourenço will investigate how leptin influences the function of regulatory T cells in lupus. Her aim is to develop strategies of leptin-based modulation of these cells in lupus. Given the importance of regulatory T cells in controlling autoimmunity, these studies have the potential to define new approaches for improved management of lupus and other autoimmune diseases.

The Scripps Research Institute

The role of cartilage-specific microRNA 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 being characterized and this has the potential to lead to new therapeuutic interventions.

Small, non-coding microRNAs are new negative regulators of gene expression and have been associated with diseases 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, microRNAs showed novel regulators of cartilage growth and development. And, changes in microRNA expression and function play an important role in OA pathogenesis. The proposed studies have the potential to reveal important new pathways that control cartilage growth. He plans to identify novel targets for OA using this strategy.

University of Chicago

Eng Tan Scholar
Genetic Regulation of Interferon Alpha Human Lupus

Lupus is a complex disease in which the body's immune system attacks its own tissues and organ systems. For the most part, it is not known why one person gets lupus and another does not. A cytokine (or immune system signaling molecule) called interferon alpha (IFN-a) is elevated in the blood of many lupus patients, and likely plays a role in the initiation of disease.

Dr. Niewold hypothesizes that some people make more IFN-a than others, and that people who make more IFN-a are at higher risk of developing lupus. This inherent tendency to make more IFN-a has a genetic component, and Dr. Niewold plans to study lupus patients to detect the genetic variations that result in abnormal IFN-a production. The information generated by this project should generate a better understand why some people get lupus, and may suggest better ways to not only treat the disease, but also possibly ways to prevent disease in high risk individuals.

Children’s Hospital Boston

John Vaughan Scholar
A novel modulator of neutrophil function in inflammatory arthritis

Neutrophils are immune cells that migrate into the joint cavity during inflammatory arthritis. Studies in mice confirm that neutrophils are absolutely necessary for the normal evolution of arthritis, but little is known about the mechanisms by which neutrophils reach the joint, what they do once they arrive, and how this can be manipulated therapeutically.

Dr. Nigrovic has found that a particular protein on the surface of mouse neutrophils appears to play a role in this process. He anticipates that these experiments will contribute to the understanding of the mechanisms by which neutrophils reach the inflamed joint, and potentially define a novel mechanism by which neutrophil recruitment can be targeted to treat inflammatory joint disease.

University of Arizona

Characterization of pathogenic Th17 responses in collagen induced arthritis

The question, “Why do we get autoimmune diseases like rheumatoid arthritis?” remains to be answered. All autoimmune disorders is associated with a dysfunctional immune system. It is thought that this dysfunction resides within the broad immune cell types or immune molecules. Recently, Th17 cells which are a subtype of immune cell have been implicated in several autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease. Additionally, Th17 cells play an important role in protecting the human body from infections. Further, if the Th17 cell is the key suspect then why is it that some people get rheumatoid arthritis, whereas others get multiple sclerosis, and others get inflammatory bowel disease? It is possible there are different subtypes on Th17 cells associated with these different autoimmune diseases. Preliminary data generated from Dr. Sarkar’s laboratory have provided some clues to this hypothesis.

Specifically, Th17 cells associated with rheumatoid arthritis are not only characterized by the key molecule they make such as IL-17, but also by the various surface molecules it expresses that target it to the joint, causing inflammation and bone destruction.

Studies outlined in this proposal will characterize the Th17 cell associated with rheumatoid arthritis in detail. Dr. Sarkar will utilize state of the art techniques much as multi-color flow cytometry, gene expression analysis, and immunohistochemistry to examine these cells.

The data obtained from this study will not only identify the pathogenic Th17 characteristics in rheumatoid arthritis but also lay the foundation for identifying and differentiating such pathogenic responses in other autoimmune diseases such as lupus, scleroderma and multiple sclerosis.