FOR IMMEDIATE RELEASE
June 10, 2004

Unraveling the Mystery of Arthritis:
Shedding Light on the Underlying Mechanisms

LONG BEACH, CA -- The Arthritis National Research Foundation proudly awarded eleven exemplary post-doctoral scientists research grants totaling $546,619 for the 2004-2005 grant cycle. The scientists are associated with top research laboratories in non-profit institutions across the country. The grant recipients received the highest priority scores determined in the NIH-level review by the ANRF’s renowned Scientific Advisory Board.

Christine Beeton, Ph.D., University of California, Irvine, Potassium Channels in Lymphocytes: Therapeutic Targets for Immunomodulation in Rheumatoid Arthritis

Under normal conditions, white blood cells such as T lymphocytes, protect the body against disease-causing mechanisms. In autoimmune diseases such as rheumatoid arthritis (RA), the body attacks self-tissues. Recent studies show that self-reactive T cells that contribute to tissue damage in RA belong to a subpopulation called “effector memory T lymphocytes.” These cells seek out and destroy tissues containing the autoantigen that triggered them.

High specificity is of real importance in biological therapy – picture this analogy: the use of precision guided bombs vs. carpet bombing. The therapy used should minimize collateral damage to the surrounding tissues and systems. Dr. Beeton’s goal is to determine if a specific protein, the Kv1.3 channel is essential for the activation of effector memory T cells. Her lab has discovered a blocker for this protein that shuts down the troublesome T cells while sparing other subsets of T cells. Dr. Beeton will test this therapy utilizing cells from the joints of RA patients, with the control group being osteoarthritis patients. In addition, they will test the efficacy of the treatment itself in reducing the severity and duration of arthritis in a rat model of RA. These proof-of-concept studies will set the stage for future evaluation of Kv1.3 blockers as a therapy for RA.

Christopher Chen, Ph.D., The Hospital for Special Surgery, The roles of TIMP-1 in cartilage degradation and repair after load-induced injury

Osteoarthritis, the leading cause for disability in the U.S., is the object of Dr. Chen’s study. OA is the breakdown of cartilage which may be triggered by minor damage from trauma. Findings from recent studies suggest that the degeneration in cartilage injured by physical trauma is due mainly to the accumulation and activation of a group of enzymes called metalloproteinases. These enzymes can breakdown collagen and other components of joint cartilage. A window of opportunity exists immediately after injury to prevent or reduce damage to the cartilage caused by these enzymes.

Recent studies in Dr. Chen’s lab and other groups show that injury-related degeneration can be prevented in a test tube by administering TIMP-1.

TIMP-1, a natural inhibitor of metalloproteinases, is also known to play an important role in preventing cancer and improving wound healing in cardiovascular tissues. In his ANRF project, Dr. Chen takes advantage of modern molecular biology and gene therapy to study how the lack of TIMP-1 protein may affect the degenerative and repair processes of injured cartilage. He will also study whether the increasing TIMP-1 could prevent cartilage degeneration and benefit cartilage repair right after joint injury. Whereas previous studies by Dr. Chen’s group have been performed using isolated tissues in a test tube, this study will examine intact joints. Dr. Chen anticipates that the findings will provide novel insights on the role of TIMP-1 in cartilage degeneration and on treating damaged cartilage in osteoarthritis and other types of arthritis.

Kemin Chen, M.D., Ph.D., University of Missouri-Columbia School of Medicine, Role of Chemokines and matrix metalloproteinases in resolution vs. fibrosis in a murine model of granulomatous experimental autoimmune thryoiditis (G-EAT): implications for pathology and treatment

Fibrosis, or scarring, is a relatively common complication in rheumatic diseases and is often considered to be an irreversible process, usually treated with anti-inflammatory and/or immunosuppressive drugs. This type of therapy is not very effective and may have serious side effects. Dr. Chen will conduct a detailed study of how autoimmune processes lead to tissue fibrosis and how to reverse fibrosis after it develops, utilizing a mouse model.

Studying the fibrosis process versus the healing process may offer novel therapeutic strategies on how to remove unwanted scarring in diseased organs, including joints, to alleviate the suffering of patients with fibrotic diseases.

Walter Fast, Ph.D., University of Texas at Austin, Peptidylarginine Deiminase IV: Enzymology of a Rheumatoid Arthritis Susceptibility Gene Product

Rheumatoid arthritis is a chronic inflammatory condition affecting almost 1% of the world’s population. The etiology of this complex disease is still unknown. However, considerable research interest has focused on the appearance of disease specific autoantibodies that recognize a subset of our own proteins, containing a modification called citrulline. Some of the most specific forms of rheumatoid arthritis autoantibodies recognize citrullinated proteins, appear very early in the disease, and are predictive of clinical outcome. A strong association has recently been discovered between susceptibility to rheumatoid arthritis and mutations in a gene responsible for protein citrullination.

Dr. Fast will seek to determine whether these mutations introduce any functional changes into the activity or calcium regulation of this important enzyme, PAD4. In addition, these studies will lay the groundwork for future studies of PAD4 and for the design of small molecule inhibitors that could potentially be used for developing therapeutic drugs.

Jon Giles, M.D., The Johns Hopkins University School of Medicine, Effect of TNF inhibitors on left ventricular structure and function in patients with Rheumatoid Arthritis

Dr. Giles is the 2004 recipient of the Sontag Foundation Fellowship of the Arthritis National Research Foundation. This is fourth such special award thanks to the generous sponsorship of The Sontag Foundation of Jacksonville, Florida and their commitment to supporting rheumatoid arthritis research. Lean more about The Sontag Foundation’s work at www.sontagfoundation.com.

Congestive heart failure (CHF) is more prevalent in people with rheumatoid arthritis (RA) than in comparable people without RA. Blood levels of TNF-a, an inflammatory cytokine, are elevated in both RA and CHF in people without RA. Many studies demonstrate that TNF-a is directly toxic to the heart, causing CHF when administered to experimental animals; consequently, blocking TNF reverses CHF in these animals. However, TNF inhibitors have been shown to be ineffective, or even harmful, when administered to people with advanced CHF. Moreover, a handful of reports in people with RA have implicated TNF inhibitors in cases of new onset or worsened CHF.

In order to address these seeming contradictions, Dr. Giles will investigate the effect of one TNF inhibitor, infliximab, on heart muscle structure and function in 20 RA patients with no history of CHF using cardiac MRI before and after treatment. He anticipates that the use of TNF inhibitors prior to the development of symptomatic CHF will be associated with a slowing of the cardiotoxic effects of TNF-a encountered in active RA. This study will help clarify current controversies regarding the prescribing of this class of medications. In addition, by using this sensitive imaging technique, novel insights will be gained about the effect of TNF-a on the rheumatoid heart.

Christine Grimaldi, Ph.D., Albert Einstein College of Medicine, The role of estrogen receptors in
B cell mediated autoreactivity

Dr. Grimaldi’s study focuses on systemic lupus erythematosus (SLE), an autoimmune disease caused by the production of autoantibodies that mediate tissue damage in target organs, such as the kidney. The autoreactive B cells that secrete autoantibodies are generated in healthy individuals; however, they do not cause disease because the healthy immune system is able to regulate these cells. Dr. Grimaldi will study how the autoreactive B cells of SLE patients bypass the surveillance mechanisms of the immune system.

Since SLE affects females almost 10 times more frequently than males, it has been widely speculated that estrogen plays a role in disease progression. To learn more about the effects of estrogen in SLE patients, Dr. Grimaldi has been treating mice with estrogen. The data accumulated have shown that an increase in estrogen induces a lupus-like disease in mice, indicating that elevations of estrogen levels are sufficient to alter the regulation of autoreactive B cells. Her ANRF study will focus on estrogen receptors, trying to determine the effects of different receptors on the survival and activation of autoreactive B cells. This may have important clinical applications: selective estrogen receptor modulators could be developed to counteract the estrogen receptor identified as integral for progression of SLE.

Koichi Kobayashi, M.D., Ph.D., Yale University School of Medicine, Role of AHNAK in calcium signaling in T lymphocytes

The most recently developed treatments for autoimmune diseases such as rheumatoid arthritis or lupus are based on regulation of an uncontrolled immune system by immunosuppressive drugs. However, these drugs are often toxic with undesirable side effects. The development of more advanced drugs, with strong immunosuppression, low toxicity and fewer side effects is necessary.
Many immunosuppressive drugs like Cyclosporine A or FK506 (tacrolimus) affect calcium signaling in T lymphocytes. Although there have been many efforts to reveal the mechanism of calcium signaling in T lymphocytes, the function of calcium channels on T cell membranes, which transport calcium into the cell, is poorly understood. Dr. Kobayashi’s lab recently found that a large molecule, called AHNAK, is interacting with calcium channels in T lymphocytes and is required for normal calcium signaling. Dr. Kobayashi’s team will reveal the mechanism of calcium regulation by AHNAK using a mouse model which is lacking the AHNAK gene. These studies should significantly contribute to the understanding of calcium signaling in T cells, which is critical to develop more effective therapies for autoimmune diseases.

Susan Kovats, Ph.D., Beckman Research Institute/City of Hope, Plasmacytoid dendritic cell production of IFN-alpha in lupus prone mice

Dr. Kovats will be working with former ANRF grant recipient, Chaim Jacob, M.D., Ph.D., of the University of Southern California to study the role of the cytokines, interferon-alpha (IFN), tumor necrosis factor (TNF) and immune cells termed dendritic cells, during onset and progress of lupus-like disease in lupus prone-mice. Excess IFN is thought to contribute to the immune cell dysfunction in lupus. Normally, this IFN production by dendritic cells would be turned off by TNF. Lupus-prone mice have low levels of TNF due to a genetic alteration, and systemic treatment of these mice with TNF reduced lupus progression and severity.

Ultimately, these experiments will lead to a greater understanding of the biological mechanisms behind the effects of TNF and IFN in lupus patients, thus aiding future strategies of immune intervention in SLE.

Meera Ramanujam, Ph.D., Albert Einstein College of Medicine, Effects of BAFF and APRIL Blockade on B cells in Murine Antiphospholipid Syndrome

Lupus is an autoimmune disease in which B lymphocytes make autoantibodies that deposit in the kidney and may lead to kidney damage. Another major complication in lupus patients is a clotting tendency associated with development of antiphospholipid antibodies.

Dr. Ramanujam plans to study the mechanism of blocking a molecule termed BAFF thought to be overexpressed in lupus patients. Her preliminary experiments have shown that blocking BAFF prevents blood clots in mice that spontaneously develop lupus. Her ANRF project will focus on determining whether these soluable BAFF blockers can be used as a therapy for antiphospholipid syndrome. (Blockade of BAFF is a strategy that is already being used to treat patients in clinical trials of SLE.)

Masanao Tsuda, Ph.D., The Scripps Research Institute, Transcriptional regulation of chondrogenesis via histone modifications

Osteoarthritis (OA) is the disease characterized by progressive joint destruction without regeneration of new cartilage. Regeneration of cartilage relies on appropriate control of chondrocyte development, whose process is tightly regulated by gene expression. Despite significant progress in identification of important factors regulating gene expression in chondrocyte development, the insight into the mechanism of how these factors function has been limited. One reason is the lack of analysis of how these factors access DNA. Since DNA is stored by “histone”, they usually restrict the access to information in DNA. Modifications that change histones allow contact with DNA and lead to gene expression. A certain set of modifications is thought to form a code, which specifies a pattern of gene expression (known as the Histone Code).

This proposal will seek to decipher the Histone Code in cartilage development and to apply data on cartilage regeneration. With the planned experiments, Dr. Tsuda expects to advance understanding of cartilage cell biology and to generate the basis for new insight into the pathogenesis and treatment of cartilage disorder. Research on the molecular mechanism of chondrogenesis will advance the understanding of skeletal development and has the potential to identify new approaches to the treatment of joint diseases.

Jingsong Wang, M.D., Harvard School of Public Health, Mechanisms of Action of the Transcription Factor T-bet in Dendritic Cells

T helper lymphocytes are of two different types, called T helper 1 and T helper 2. They are defined in that manner because they make different kinds of small polypeptide mediators, called cytokines. It is clear that T helper 1 cells contribute to and worsen autoimmunity, while T helper 2 cells improve autoimmunity. Recent work suggests that dendritic cells of the innate immune system, contribute significant polarizing influences on the development of the T helper types. Most recently, it has been shown that dendritic cells play a crucial role in the development of inflammatory arthritis. Furthermore, this dendritic function is controlled by a novel gene, called T-bet, which was isolated in Dr. Wang’s laboratory. In an inflammatory arthritis mouse model, dendritic cells expressing T-bet cause arthritis. Therefore, T-bet provides an attractive new target for the development of novel therapeutics for inflammatory arthritis.

Dr. Wang will use systemic approaches to analyze how T-bet exerts its function. Various approaches, including genetically mutated mice, will be utilized to identify potential target genes for T-bet in dendritic cells. He anticipates gaining a better understanding of the mechanisms of T-bet function in dendritic cells. These studies may permit the design of therapeutic agents that manipulate the relevant signaling pathways in dendritic cells to control inflammation with much higher efficiency.

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