New Therapeutic Target for Lupus
David Cauvi, Ph.D., The Scripps Research Institute, La Jolla, CA
Decay accelerating factor and systemic autoimmunity

Systemic lupus erythematosus (SLE or lupus) is a devastating chronic autoimmune disease affecting multiple organ systems and characterized by a broad array of antibodies. Dr. David Cauvi’s laboratory has identified that a protein called decay accelerating factor (DAF), is increased in lupus-resistant mice. Dr. Cauvi will test whether an elevated level of DAF reduces the development of SLE by treating lupus-prone mice with DAF. At the completion of these experiments, Dr. Cauvi hopes to discover whether or not DAF plays a protective role in the development of SLE. If so, this provides a new target for therapeutic intervention, not only for SLE but for other autoimmune diseases, as well.

Using a New Genetic Tool
Hongbo Chi, Ph.D., Yale University School of Medicine, New Haven, CT
S1P1 and regulation of autoimmune disease

T lymphocytes, a type of white blood cell, play a central role in the regulation of immune responses against infection. The function of T lymphocytes is critically dependent upon their ability to distinguish between self and non-self. The inappropriate recognition of self tissues by T lymphocytes leads to many autoimmune diseases; the most representative systemic autoimmune disease in humans is systemic lupus erythematosus (SLE or lupus). Therapeutic intervention of SLE and other rheumatic diseases requires a better understanding of the molecular and cellular pathways regulating T cell function. Dr. Hongbo Chi is using a new genetic tool to study this molecular pathway in immune responses and autoimmune diseases with the long-term goal of translating the knowledge gained from these studies into innovative therapeutic strategies.

Proteins that may cause RA
Myung-Shin Jeon, Ph.D., La Jolla Institute for Allergy and Immunology, San Diego, CA
c-Cbl in the development of autoimmune arthritis

T cells are the critical components in the initiation and the maintenance of autoimmune diseases, such as rheumatoid arthritis. Dr. Myung-Shin Jeon will analyze mice with collagen-induced arthritis to understand the molecular function of certain proteins in the development of arthritis. This may help identify novel therapeutic approaches for the treatment of human autoimmune arthritis (RA) and other autoimmune disorders.

Gene Therapy for Lupus
Martin Kriegel, M.D., Yale University School of Medicine, New Haven, CT
T Cell-specific Deletion of GRAIL – the gene related to anergy in lymphocytes

One key mechanism to preserve normal immune response – called T cell anergy – is disturbed in SLE patients and lupus-prone mice. The molecular details of anergy are not fully understood. Dr. Martin Kriegel’s study will examine a particular enzyme in the anergy pathway called gene related to anergy in lymphocytes (GRAIL). He will genetically engineer a mouse so that GRAIL is not expressed, specifically in T cells, to study its role in the development of SLE and other systemic autoimmune diseases. In the long term, enzymes like GRAIL may provide novel therapeutic avenues for rheumatic diseases.

The Role of B Cells in RA
Taras Lyubchenko, Ph.D., University of Colorado Health Sciences Center, Denver, CO
Role of complement receptor 2 (CR2/CD21) in B cell receptor signal transduction

Understanding the mechanisms underlying activation of antibody-producing B cells is particularly important in autoimmune diseases such as rheumatoid arthritis. Dr. Taras Lyubchenko’s study will focus on one of the key processes responsible for the contribution of B cells to the course of the autoimmune disease – intracellular signaling mechanisms. The goal of this study is to characterize these novel mechanisms of B cell activation and to facilitate a new therapeutic approach to reduce B cell activation in rheumatoid arthritis.

Understanding the Immune System
Adam Mor, M.D., New York University School of Medicine, Hospital for Joint Diseases, New York, NY
Ras signaling in Autoimmune T cells: Spatiotemporal Ras signaling in primary T cells

The immune system is designed to protect us from infection, but when its regulation is impaired it can give rise to diseases in which normal tissues are damaged. Lupus (SLE) is the prototype of such a disease. The component of the immune system that regulates its activity is a type of white blood cell called a lymphocyte. Like all cells, a complex network of regulatory proteins controls the activation of a lymphocyte. Among the most important of these is one called Ras. Ras functions as a simple molecular switch (“on” versus “off”). Recently, a strain of mice that develop lupus was found to have defective control of Ras. Dr. Adam Mor developed novel tools to study when and where Ras becomes active in living cells. He will apply these tools to lymphocytes from normal and lupus mice to learn what aspects of Ras activation are relevant for the development of the disease. In order to prevent onset of the disease, we must understand the defects at the molecular level. Learning the basic pathways involved in the pathology of lupus is a crucial step in the development of drugs against the disease.

Cartilage Regeneration in OA
Anna Spagnoli, M.D., Vanderbilt University Medical Center, Memphis, TN
Role of insulin-like growth factor (IGF-I) in mesenchymal stem cell cartilage regeneration

In industrialized countries, osteoarthritis affects over one-third of the adult population. Since cartilage is unable to repair itself, treatments for osteoarthritis primarily cover up symptoms only. This had led to efforts to develop alternative means to restore degenerated cartilage. Over the last few years, research in tissue regeneration has been bolstered by the discovery that cells in bone marrow, called mesenchymal stem cells (MSC), are capable of maturing into several tissues including cartilage. Dr. Anna Spagnoli’s research is aimed at understanding the mechanisms by which growth factors regulate MSC cartilage regeneration potential. Among these growth factors, insulin-like growth factor-I (IFG-I) seems to play a pivotal role in cartilage regeneration. The primary focus of Dr. Spagnoli’s study is to define the mechanisms by which IGF-I determine the cartilage potential of MSC. Identification of such mechanisms will provide a critical framework to fully implement and optimize effective MSC gene and cellular therapy in patients with osteoarthritis.

Preventing Bone Loss in RA
Nicole Cherie Walsh, Ph.D., Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, Boston, MA
The role of T cells in the pathogenesis of focal articular bone loss in inflammatory arthritis

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, with osteoclast resorption predominating. This results in bone loss within the joints leading to joint deformity and pain. The exact mechanisms mediating this imbalance have not been fully explained. White blood cells such as T cells not only contribute to inflammation within the RA joint, but have also been implicated in mediating the formation of osteoclasts. There is also evidence to suggest that T cells may modulate osteoblast formation and function. Therefore, T cells represent a potential target for therapeutic intervention to prevent arthritis-induced bone loss.

Dr. Nicole Walsh’s study will assess the potential for the T cells to modulate osteoblast formation and function in arthritis, using experimental animal models of arthritis. A clearer understanding of the role of T cells in mediating arthritis-induced bone loss may lead to the development of novel therapeutic strategies to prevent bone loss in this disease.

Novel Imaging Technique
Xueding Wang, Ph.D., University of Michigan, Ann Arbor, MI
Photoacoustic tomography of inflammatory arthritis

The 2005-2006 Sontag Foundation Fellowship award recipient, Xueding Wang, Ph.D., developed a new technique using laser technology to provide images of soft tissues such as joints affected by arthritis. He will test the technique (which has already been demonstrated successfully in brain images) in animals, comparing the non-invasive images with physically sectioned tissue to determine the efficacy of the imaging technique.

The objective of this proposed research is to develop a novel, non-ionizing, non-invasive, laser-based technology-- photoacoustic tomography (PAT) - to image structural and functional changes in inflammatory joint diseases. PAT can image tissue structures and functional changes with high resolution and may provide a unique opportunity for early diagnosis and monitoring of therapeutic interventions in inflammatory arthritis with high specificity. Although PAT will be tested on animals, the ultimate goal is to develop an imaging technology for human joints. This technique is non-invasive, cost-effective, minimally-dependent on operators, and patient-friendly. PAT has the potential to become a routinely used bedside tool for rheumatologists in the near future.

Dr. Wang is the fifth recipient of The Sontag Foundation Fellowship, an honor bestowed after a second, in-depth review of all ANRF grant recipients by The Sontag Foundation of Ponte Vedra Beach, Florida. They are committed to supporting research with the maximum potential to benefit those suffering with rheumatoid arthritis. Learn more about The Sontag Foundation’s work at www.sontagfoundation.com.

Alternative to Immunosuppressive Drugs
Song Guo Zheng, M.D., University of Southern California, Los Angeles, CA
Effects of TGF-B on both CD4+ and CD8+ cells are required for optimal generation and function of regulatory cells

Certain cells that respond to self tissues or organs exist in normal humans; however, their activities are controlled by a cell population called regulatory T cells. The deficit and dysfunction of regulatory T cells cause autoimmune diseases. This novel knowledge provides a possibility that regulatory T cells can replace immunosuppressive drugs to treat autoimmune diseases.

Dr. Song Guo Zheng will study the effects of different combinations of regulatory T cells, generating results that will provide guidance to choose optimal combination of regulatory T cells in the therapy for SLE patients.
In Dr. Zheng’s opinion, it is likely that regulatory T cell therapy will one day replace the immunosuppressive drugs currently used to treat autoimmune diseases and for patients who have had organ transplants. The regulatory T cells might be more effective and less toxic.

Second-Year Grant Recipients: The Research Continues
For the first time this year, the ANRF has awarded a second year of funding to several scientists. Each submitted a detailed report outlining the scientific progress made during the first year of their study and a formal proposal for continuing the work for a second year.

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

Fibrosis is the cycle of damage-healing-scarring-damage, etc. in inflammatory disease. The functions of various proteins and peptides are to direct specific inflammatory cells to the diseased tissue and to regulate formation and breakdown of fibers in scars. Research has shown that fibrosis progresses in some mice, but other affected mice return to normal, suggesting that healing mechanisms exist to end inflammation and clear the scarring, thereby reversing fibrosis.

The results of Dr. Kemin Chen’s study will be 1) to determine if fibrosis derives from dysregulated proteins and peptides in the study, and 2) to design therapeutic strategies to inhibit development of fibrosis by blocking the specific proteins and peptides (chemokines and MMPs).

RA Gene Susceptibility Study
Walter Fast, Ph.D.,
The University of Texas at Austin
Peptidylarginine Deiminase 4: Enzymology of a Rheumatoid Arthritis Susceptibility Gene Product

Rheumatoid arthritis is a chronic inflammatory condition affecting almost 1% of the world’s population. The cause of this complex disease is still unknown. However, considerable research interest has focused on the appearance of disease specific autoantibodies in RA that recognize a subset of our own proteins that contain an unusual modification called citrulline.

Dr. Fast’s lab is studying the mutations in this gene that may result in changes to the normal activity, regulation, localization, or specificity of its product, an enzyme that catalyzes protein citrullination. He is comparing this enzyme and the mutant enzyme associated with rheumatoid arthritis susceptibility to determine whether these mutations cause changes in the activity or regulation of this important enzyme. He is also synthesizing and studying new small molecules that can inhibit the activity of the enzyme. In the future, these small molecules could potentially be used in the design of new drugs to treat rheumatoid arthritis.

Increased Estrogen May Alter
Immune Response
Christine Grimaldi, Ph.D., Columbia University Department of Medicine, New York, NY
The role of estrogen receptors in B cell autoreactivity

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the production of autoantibodies that may cause tissue damage of target organs, such as the kidney. The B cells that secrete autoantibodies are generated in healthy individuals; however, they are unable to cause disease because the immune system is able to effectively regulate these cells. Dr. Christine Grimaldi is studying how the autoreactive B cells of SLE patients bypass the surveillance mechanisms of the immune system that would normally silence these cells in healthy individuals.

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 on the regulation of B cells and the production of autoantibodies, Dr. Grimaldi has been treating mice with estrogen. The resultant data have shown that an increase in estrogen induces a lupus-like disease in treated mice.

These studies have important clinical implications since selective estrogen receptor modulators can be developed that specifically antagonize the estrogen receptor identified as being important for disease progression. Such clinically focused therapies may prove to be beneficial for treating patients with an estrogen responsive form of SLE

Molecular Pathways to Safer Autoimmune Treatments
Koichi Kobayashi, M.D., Ph.D., Harvard University Dana-Farber Cancer Institute, Boston, MA
Role of AHNAK in calcium signaling in T lymphocytes

Current 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.

The function of calcium channels on T cell membranes, which transport calcium into the cell, is poorly understood. Dr. Koichi Kobayashi recently found that a large molecule, called AHNAK, is interacting with calcium channels in T lymphocytes and is required for normal calcium signaling. His study will reveal the mechanism of calcium regulation by AHNAK using a mouse model which is lacking the AHNAK gene. These studies should contribute significantly to the understanding of calcium signaling in T cells, which is critical to developing better treatments for autoimmune diseases.