Previous Grant Recipients

Autoimmune diseases, including Rheumatoid Arthritis (RA), occur when the immune system mistakenly attacks the body’s own tissues. This complex system of cells and antibodies normally destroys “invaders” such as viruses and infections. Unfortunately, RA patients have immune cells and antibodies in their blood that attack their own tissues.

In this project, Dr. Kim evaluates the ability of a recently identified cell population, termed CD8+ regulatory T cells, to suppress or block RA progression. Using novel strategies, Dr. Kim will examine the potential therapeutic effects of this cell-based treatment to ameliorate or prevent RA.

Osteoarthritis (OA) affects more than100 million individuals worldwide and causes chronic and severe pain in knee joints. It is not clear what causes pain in OA, nor is there an effective way to relieve the pain. Understanding mechanisms of pain caused by OA is essential to finding more effective treatments.

Micro-RNAs are small RNA molecules that regulate gene expression. Using established knee joint OA pain animal models and molecular biological methodology, Dr. Li is studying the links between selected micro-RNAs and knee OA pain. This study seeks to identify the mechanisms responsible for OA-associated knee joint pain, then use targeted inactivation of selected micro-RNAs to lessen pain symptoms.

Regulatory T cells (Treg) are an immune cell population that plays an active role in protecting humans against rheumatoid arthritis. The delivery of drugs specifically to Treg to boost their activity is highly desirable since it could lead to more efficient therapies against rheumatoid arthritis. However, there is still no approach to deliver drugs into specific immune cell populations in living animals.

Dr. Massimo Bottini has developed chemically engineered nanoscopic particles which can efficiently and safely bring pharmaceutical and diagnostic agents into selected cells in living animals. In this clinical study, he is targeting drug delivery only to Treg, and he predicts that new approaches and lower doses of drugs can be used, thereby opening new avenues for low-risk treatment and/or prevention of rheumatoid arthritis.

At Brigham & Women’s Hospital (Harvard’s teaching hospital), Dr. Ercan is studying the role of the modified antibodies found in both juvenile and adult arthritis patients in the cause and tissue destructive phase of the disease. His work may lead to better understanding juvenile and adult rheumatoid arthritis and provide novel targets for new therapies.

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 biologic therapies including abatacept and anti-TNF therapies can improve vessel wall inflammation and plaque characteristics in RA patients. The results of this study will help determine potential risk reduction strategies for CV disease in patients with RA.

Systemic lupus erythematosus (lupus) is an autoimmune disease that can result in such devastating outcomes as renal failure and death. Treatment strategies for severe lupus rely heavily on medications that are relatively non-specific and carry a heavy burden of morbid side effects. In order to generate more targeted therapies, a more refined understanding of disease progression is needed.

It has been suspected for decades that B cells must play a critical role in disease. Indeed, human and mouse genetic and biochemical studies suggest that lupus is characterized by B cells with abnormal antigen receptor signaling. (An antigen is any substance that causes the immune system to produce antibodies against it.) Most recently, novel biologic therapies targeting B cells have been approved for lupus patients. Yet the mechanisms by which abnormal signaling through the B cell antigen receptor (BCR) produces systemic autoimmune disease remain ill-defined.

Dr. Zikherman’s study using mice will define the biochemical and cellular mechanisms involved to show how abnormal BCR signaling drives lupus progression in humans. The results may suggest more effective targets for treatment.

Cardiovascular Biomarkers That May Confer Increased Risk of Atherosclerosis in Psoriasis and Psoriatic Arthritis

Arthritis National Research Foundation, in collaboration with the National Psoriasis Foundation awarded a two-year translational research grant to Elaine Husni, M.D., M.P.H., of the Cleveland Clinic in Ohio. Dr. Husni will examine evidence that psoriatic arthritis patients are at increased risk for heart disease by studying the connections between joint inflammation and cardiovascular inflammation.

Psoriasis and psoriatic arthritis is a disease with increased morbidity and mortality, and this is largely due to cardiovascular disease. The ability to predict and prevent cardiovascular disease in these patients is one of the most exciting and fastest-growing areas of medical research today. With so many advances in cardiovascular risk reduction in the general population, these concepts have only begun to surface in the study of psoriatic diseases.

This study will help identify and characterize the cardiovascular biomarkers in psoriasis and psoriatic arthritis that may allow earlier detection of those patients at risk for atherosclerosis (heart disease). This grant enables a cohesive team of scientists in rheumatology, dermatology and cardiology to come together to conduct innovative research that would not traditionally be possible.

Genetic risk factors are known to be a major contributor for developing lupus. The complement system, a biochemical cascade found in blood circulation that participates in the immune system to help clear disease-causing bacteria, plays a pivotal role in lupus.

In the first year funded by ANRF, Dr. Zhao reported that a genetic variant, the deletion of two complement regulatory genes (CFHR1 and CFHR3), were more frequently found in lupus patients than in healthy people, indicating that genetic deficiency of these two genes predisposes to lupus. In the second year, Dr. Zhao will investigate the functional consequence of the deletion of CFHR1 and CFHR3 in lupus patients.

The studies into the role of these genes in the disease progression of lupus may lead to the development new therapies in the future.

Patients suffering from rheumatoid arthritis and lupus often develop cardiovascular disease at much younger ages than healthy people. This could be due in part to a dysfunctional form of HDL (the “good cholesterol” responsible for preventing inflammation and clogged arteries) present in almost half of lupus patients and one quarter of RA patients, but generally absent from people without autoimmune diseases (< 5%). We do not understand how this dysfunctional, pro-inflammatory HDL (piHDL) promotes cardiovascular disease in RA and lupus, but we do know that piHDL activates monocytes, the main immune cell involved in forming the plaque that clogs arteries.

Recent experiments suggest piHDL might differ from normal HDL in composition. Dr. Skaggs will examine piHDL isolated from RA and lupus patients for similarities and differences compared to each other as well as to piHDL isolated from healthy controls. Results from these studies may pinpoint abnormal levels of HDL and proteins in the body that could be targeted to reverse the effects of piHDL and block piHDL-mediated accelerated cardiovascular disease in RA and lupus.

Ankylosing spondylitis (AS) is a progressive arthritis involving the spine that causes significant disability and decreased quality of life. Current therapy is suboptimal and best when given early in the disease process. Definitive diagnosis requires evidence of damage on X-ray; thus, the time between first symptoms and diagnosis averages 8-10 years. A better understanding of the disease will lead to earlier diagnosis and more efficacious therapy.

Multiple genes contribute to the development of AS: HLA-B27 confers about 40% of the risk. Other possible contributing genes include IL-1 related genes and the IL-23 receptor. Both IL-1 and IL-23 belong to the family of proteins called “cytokines” that drive inflammation in the body. IL-23 in particular has been increasingly implicated as a cause of AS. Dr. Smith has exciting new data showing that AS patients produce too much IL-23 in response to infections. Thus, the overproduction of this cytokine in response to infections may predispose select individuals to develop AS.

Dr. Smith’s study will confirm her initial findings and determine if AS macrophages overproduce IL-23 and other inflammatory cytokines in response to a variety of infection-related stimuli. The better understanding of excess IL-23 production may lead to the development of new types of therapies for AS.