Beyond TNF: A Newly Discovered Cytokine may provide new target for RA Therapy
Christopher Benedict, Ph.D., La Jolla Institute for Allergy and Immunology, San Diego, CA

Tumor necrosis factor (TNF) is a cytokine produced by the body’s immune cells that fuels the process of inflammation in rheumatoid arthritis (RA). Blocking TNF is the best current treatment for RA. Dr. Benedict is studying a newly discovered cytokine network that is a close relative of TNF and may contribute to the initiation and/or severity of RA. Using mouse models, he hopes to generate information about neutralizing this new network that could lead to new clinical treatments for RA.

Dr. Benedict is this year’s Eng Tan Scholar, so honored for his innovative approach to studying inflammatory arthritis.

A New Model for Treating Scleroderma
Edwin Chan, M.D., New York University School of Medicine, New York, NY

Scleroderma is a devastating rheumatic disease affecting many different organs in the body. Unfortunately, there is no effective treatment known at this time. One of the most significant manifestations of scleroderma is thickening of the skin, or dermal fibrosis. This widespread, uncontrolled production of scar tissue not only results in cosmetic disfigurement, but may severely limit daily activity.

Dr. Chan has identified a molecule, adenosine, which plays an important role in dermal fibrosis. Adenosine binds to a specific receptor on the surface of the cell to produce the scarring effect. By blocking these cell surface receptors, Dr. Chan has substantially reduced fibrosis in animal models, providing a new model for treatment. His ANRF-funded study will explore the way adenosine alters fibrosis in the skin. He hopes that the results from this work will lead to novel therapeutic options to treat and prevent scleroderma.

Autoimmune Disorder Target: DRAK2
Martina Gatzka, Ph.D., University of California, Irvine, CA

This is Dr. Gatzka’s second year of work in autoimmune disorders, studying the body’s natural surveillance mechanisms. When T lymphocytes (T cells), a type of white blood cell, cannot distinguish between self and non-self tissues, they contribute to inflammation and tissue destruction in autoimmune diseases such as RA, lupus, and MS. Dr. Gatzka is studying a particular surveillance mechanism that keeps T cells from going awry called DRAK2 (DAP-related apoptotic kinase-2). Her research applies cutting-edge immunological and molecular biological methods to investigate how a DRAK2 modulates T cell activation and tolerance in a mouse model of rheumatoid arthritis, collagen-induced arthritis (CIA).

Identifying strategies to specifically block and eliminate self-reactive T lymphocytes is key to the development of efficient new therapies for these immune mediated diseases.

Are you susceptible to RA? It may be in your genes…
Alyssa Johnsen, M.D., Ph.D., Joslin Diabetes Center, Boston, MA

Rheumatoid arthritis (RA) is caused by a complex set of environmental and genetic factors. Currently, only a small number of the genes that increase a person’s risk of developing RA have been identified. Discovering additional genes that control RA would help us understand what causes the disease and how to more effectively treat or even prevent arthritis.

Dr. Johnsen will use a unique group of mice to help find the genes controlling inflammatory arthritis. Once she treats the mice so that they develop arthritis, Dr. Johnsen can then correlate the presence of a particular DNA sequence at a specific location on the genome with the severity of the arthritis. This will identify the location of the genes that are controlling arthritis in these animals. Given the similarity of the mouse model with human RA, it is likely that these genes also play a significant role in the human disease. Finding genes controlling susceptibility to RA will enhance our understanding of how the disease works and will potentially identify new targets for pharmaceutical development.

Dr. Johnsen has been named the first John Vaughan Scholar, in honor of her excellence in rheumatoid arthritis research. Dr. Vaughan was an ANRF grant recipient in the 1970s, past president of the American College of Rheumatology, and world-renowned researcher, clinician and professor. We mourn his passing in 2006.

Lupus Therapy Without Toxicity
Hee Kap Kang, Ph.D., Northwestern University, Chicago, IL

Dr. Kang has developed a therapy to repair a cell defect which may cause lupus. To test this therapy, Dr. Kang’s lab is studying the effects of injecting a specific peptide into a lupus-prone mouse.

The peptide therapy appears to be beneficial without any toxic effect so far, and thus might be very important in maintaining tolerance in lupus patients after remission has been induced by more toxic immunosuppressive agents. Even apparently healthy subjects and family members of lupus, who might be at risk of developing lupus (as predicted by genetic and biomarkers) might benefit from the peptide therapy.

This is the second year ANRF has funded Dr. Kang’s work. In recognition of his exemplary studies, he has been awarded the honor of being named the first James Klinenberg Scholar. James Klinenberg, M.D., was a founding member of the ANRF Scientific Advisory Board, past president of the American College of Rheumatology, and world-renowned researcher and clinician in rheumatic diseases. Sadly, Dr. Klinenberg died in 1999.

Understanding Bone Loss in RA
Sougata Karmakar, Ph.D., University of Massachusetts Medical School, Worcester, MA

Rheumatoid arthritis (RA) is a chronic, debilitating disease that affects the joints in patients and may result in bone loss. The structural integrity of bone is maintained by the coordinated actions of two cell types, the bone-forming osteoblast and the bone-resorbing osteoclast. In rheumatoid arthritis (RA), there is an imbalance in the activities of these two cells, resulting in bone loss leading to joint deformity and pain.

Dr. Karmakar will study bone morphogenetic protein (BMP) in arthritic mice, hoping to demonstrate that an antagonist of BMP inhibits osteoblast maturation and function at bone erosion sites in RA joints, resulting in impaired bone formation. Understanding these mechanisms will allow for the identification of novel targets to augment bone formation at erosion sites, a necessary step to preserve joint function in RA.

Dr. Karmakar has been honored as The Sontag Foundation Fellow for 2007-2008, for excellence in research related to rheumatoid arthritis.

Growth Factors in Cartilage Cells: A Novel Therapy
Chuanju Liu, Ph.D., New York University School of Medicine, New York, NY

The molecular mechanisms controlling cartilage formation, and specifically those relating to the osteoarthritis, are still unclear. It is believed that specific growth factors and surrounding matrix proteins play critical roles in controlling cartilage formation and the progression of osteoarthritis. Dr. Liu’s recent research led to the discovery of granulin/epithelin precursor (GEP), a novel growth factor in cartilage and a therapeutic target in arthritis. The primary focus of Dr. Liu’s ANRF study is to determine the role of GEP in the differentiation and metabolism of cartilage cells. He hopes this study will enhance our understanding of growth factors in cartilage and their application to the treatment of arthritis.

From Stem Cells to Cartilage Repair
Audrey McAlinden, Ph.D., Washington University School of Medicine, St. Louis, MO

Articular cartilage is an essential component of our joints, providing a lubricating, low-friction, gliding surface. This tissue contains no blood supply and so displays a limited capacity for self-regeneration. Strategies to promote articular cartilage growth are very important given the high incidence of osteoarthritis (OA) in the aging population. In OA, articular cartilage tissue degrades, resulting in severe joint pain and debilitation.

A promising method of treatment involves the use of adult mesenchymal connective tissue cells (MSCs). These cells can be differentiated to become cells of cartilage, bone, adipose or other tissues. Dr. McAlinden’s study tests an innovative approach to induce cartilage cell production from adult MSCs isolated from both adipose tissue and bone marrow. Her aim is to differentiate MSCs into the type of cartilage cells (chondrocytes) found only in articular cartilage of our joints. By using virus technology, Dr. McAlinden hopes to be able to select for the desired chondrocyte necessary to promote articular cartilage repair.

Understanding the Defective Immune System
Ziaur Rahman, M.D., Ph.D., Thomas Jefferson University, Philadelphia, PA

The human immune system is wonderfully efficient and complex. This system develops weapons, called antibodies, to use against viral and bacterial infections. When antibodies attack the body’s own tissue it leads to the development of autoimmune diseases such as systemic lupus erythematosus (SLE or lupus). In its later stages, SLE can lead to multi-organ system failure and death.

When a healthy immune system does not attack its own tissues, it is called “tolerance.” Patients with SLE show a loss of this tolerance. To date, we have come to understand this disease process through mouse models that develop human SLE-like diseases. Using these mouse models, Dr. Rahman will investigate how this tolerance functions and how autoantibodies (antibodies that attack self-tissues) are produced when this tolerance is defective. These studies will identify the genes involved in this defective tolerance process and help develop effective diagnostic and treatment approaches for systemic autoimmune diseases.

Genetic Factors in Lupus
Amr Sawalha, M.D., University of Oklahoma Health Sciences Center, Oklahoma City, OK

Systemic lupus erythematosus (SLE or lupus) is a chronic, relapsing autoimmune disease that affects multiple organs including the skin, joints, lungs, kidneys and brain. The disease is at least nine times more common in females. There is evidence for both genetic and environmental factors implicated in the pathogenesis of lupus; however, the exact pathogenesis of the disease remains incompletely understood.

Using a mouse model, Dr. Sawalha will study a specific gene that is over expressed in the T regulatory white cells of female but not male mice. The goal of these studies is to provide new insights into mechanisms causing lupus, and identify new approaches to the treatment of this sometimes fatal disease.

T Cells: Using Your Own Cells to Fight Lupus
Brian Skaggs, Ph.D., University of California, Los Angeles

Antibodies produced by immune cells in lupus patients inappropriately bind to many different self-molecules, leading to the tissue destruction throughout the body seen in the disease. Patients and researchers are, not surprisingly, frustrated that there has not been a new FDA-approved lupus therapy regimen in over thirty years. This underscores the urgent need for new, innovative lupus therapies.

Recent work by many labs, including Dr. Skaggs’ lab, has demonstrated that a particular immune cell, the regulatory T cell, can be activated by multiple mechanisms to attack the autoimmune cells that cause lupus and render them ineffective. These exciting studies are tempered by our lack of understanding as to how we could manipulate these “good” immune cells to destroy the “bad” autoimmune cells. Dr. Skaggs’ laboratory has identified a novel way to turn on the “good” regulatory T cells in a mouse model of lupus. He will study how regulatory T cells work by deciphering the intracellular networks necessary to activate these cells. Regulatory T cells have the potential to be a novel, safe method of controlling, and hopefully curing, lupus and other autoimmune diseases.

New OA Therapy Could Halt Cartilage Destruction
Ilse-Gerlinde Sunk, M.D., Harvard School of Dental Medicine, Boston, MA

Osteoarthritis (OA), the most common rheumatic disease, is the major cause of disability in the U.S. It is critical to broaden our understanding of articular cartilage at different stages of the disease to better understand OA’s development and progression.

Recently a specific cell surface receptor, discoidin domain receptor 2 (DDR2), has been identified in cartilage cells (chondrocytes). DDR2 binds to collagen in the cartilage and releases an enzyme that causes progressive damage to joint cartilage. This mechanism may play a key role in the development and progression of OA.

Dr. Sunk’s project aims to verify the role of DDR2 in an animal model of OA. Blocking DDR2 may give us opportunities of intervention that will slow down or even halt cartilage destruction. If effective, this will maximize the quality of life and independence for the increasing number of people with OA.

Focusing on the Cause of OA
Noboru Taniguchi, M.D., Ph.D., The Scripps Research Institute, La Jolla, CA

Osteoarthritis is the most prevalent joint disease. It begins with disruption of the cartilage surface and leads to progressive cartilage damage. Aging is the major risk factor for this form of arthritis; however, mechanisms for the initiation of the earliest cartilage damage are not known.

Dr. Taniguchi focuses on the role of a novel protein in cartilage surface and aging-dependent osteoarthritis. This information will not only be relevant to osteoarthritis but also to cartilage tissue engineering.