Home   About Us   Divisions   Ask a Med-U-Nurse   Health Library   Find a Doctor   For Physicians   Job Opportunities   Make a Difference   News & Events    News Room    Kids Connection Newsletter    Support Groups    Special Events    Parenting Newsletter    Parenting Classes    Community Classes    Grand Rounds Schedule   Research   Residents & Fellows   Your Hospital Visit 171 Ashley Ave. Charleston, SC 29425 843-792-1414 800-424-MUSC		Print Version January 2006 Children's Research Institute News Brief Bernard L. Maria, MD, MBA Executive Director Darby Children's Research Inst. Inderjit Singh, PhD Scientific Director Darby Children's Research Inst. Dr. Tomlinson Dr. Gilkeson In this first 2006 issue of Kids Connection, we feature truly outstanding clinical and research programs in childhood rheumatic diseases. The Childhood Rheumatic Diseases Center (CRDC) is involved in research into childhood rheumatic diseases from the bench to observational studies to clinical trials. Clinical trials ongoing in the CRDC are outlined in the feature article on the program led by Dr. Richard Silver. There are two other active clinical studies in childhood lupus. The first is investigating low birth weight as a risk factor for developing lupus or in developing significant comorbid diseases like high blood pressure and renal failure. Prior studies indicate that low birth weight has profound effects on later risk of developing hypertension, renal insufficiency and heart disease. There is also growing evidence that low birth weight has a lifelong effect on the immune system. We are investigating the birth weights of individuals with lupus in our cohort compared to controls, and assessing if low birth weight is a risk factor for lupus or developing a comorbid disease. The second clinical study is a collaborative study with investigators at the University of Colorado, UCLA and the University of Texas Southwestern. The goal of this study is to define risk factors for developing lupus, as well as identifying biomarkers predictive of developing lupus. This study will be performed in children of patients with lupus. The overall goal is to be able to identify high-risk individuals prior to onset of disease to allow trials of preventative therapy. We will also be assessing environmental triggers of disease, which are easier to identify by following patients prior to disease onset. A related risk factor study is in conjunction with Dr. Bruce Hollis, who is working in the Darby Children's Research Institute (DCRI) and whose work was featured in the October 2004 issue of Kids Connection. This study is defining the role of vitamin D deficiency on the immune system, specifically as a risk factor for developing lupus and/or lupus flares. We have found that most lupus patients are profoundly vitamin D-deficient and that the level of deficiency correlates with disease activity in adults and children. A replacement trial of vitamin D will help determine the dose of vitamin D necessary to replete body stores, and then assess the effect of this restoration on disease activity. Bench investigators in the DCRI program are pursuing several areas of investigation relevant to childhood rheumatic and inflammatory disease. Some of the different research foci are: The role of the transcription factor Fli1 in inflammatory diseases and in normal immune development. Fli1 controls the expression of a number of genes. Over-expression of Fli1 leads to a lupus-like disease in mice. Decreasing Fli1 expression is very effective in blocking lupus-like disease in mice. These effects of Fli1 are mediated through a particular cell of the immune system, the B cell. B cells make antibodies and are a key component of the immune system. In lupus and inflammatory arthritis, B cells are overactive. By modulating Fli1 expression, we can return B cell function to normal. The DCRI investigators are studying ways to control FLi1 expression. Fli1 is also a critical factor in the normal development of B cells. Studies in Fli1-deficient mice will allow better understanding of normal B cell development and how it is defective in autoimmune diseases and in certain malignancies like leukemia. Immune deficiencies. The most common immune deficiency in humans is IgA deficiency and common variable immune deficiency (CVID). We serendipitously discovered a strain of lupus mice that were deficient in a particular subset of antibodies called IgG3. This lack of IgG3 is due to a defect in what is called class switch recombination in B cells. Class switch recombination is a critical process in the normal adaptive immune response to infection. Defects in class switch (from IgM to IgA or IgG) lead to high rates of infection in affected individuals. In further studies, we isolated the gene in the IgG3-deficient mice that is defective. We also further determined that this gene is a likely candidate for the immune deficiency that occurs in humans. In collaboration with investigators at the University of Minnesota and the Karolinska Institute in Stockholm, Sweden, we have found that over 25 percent of individuals with IgA/CVID have a defect in this gene. Studies in the DCRI are defining how this gene works in class switch recombination and how we might manipulate it to help individuals with immune deficiencies. The role of complement in rheumatic and inflammatory disease. The complement system is a group of serum proteins that are activated in a cascade fashion by an activated immune system. Complement provides an important function in host defense by destroying pathogens and injured cells, but in many autoimmune and inflammatory disease states it can drive pathogenesis by causing injury to host organs and tissue. There are several components to our research in this area: The role of the complement system in inflammatory diseases such as juvenile arthritis and lupus. There are three pathways of complement activation: the classical, the alternative and the lectin. We have found that activation of the alternative pathway plays an important role in pathogenesis, and that specifically blocking the alternative pathway is very effective in preventing/treating a number of inflammatory diseases in mouse models of disease. These diseases include arthritis, asthma, lupus and retinitis pigmentosa. Selective blockade of different complement activation pathways is less immunosuppressive than complete complement inhibition and thus offers significant therapeutic benefits. Investigators in the DCRI, in collaboration with investigators at the University of Colorado, are developing inhibitors of the alternative pathway of complement as therapeutic agents that can be used in humans. Efforts are currently in process to bring these agents to clinical trials in the near future. Defining complement-dependent effecter mechanisms in stroke and spinal cord injury. Stroke is one of the top ten reasons for death in children and spinal cord injury predominantly affects a young population. Stroke or an impact to the spinal cord triggers a series of downstream events that lead to secondary injury of tissue and the progressive degeneration of brain tissue/spinal cord. We have shown that complement plays an important role in these secondary destructive processes. Mice with certain complement deficiencies are protected from brain/neuronal injury following stroke and spinal cord injury, and they have significantly improved functional scores over time compared to control mice. It has also been shown that complement activation products in these disease states (and also other inflammatory states) drive other inflammatory processes, including upregulation of various cytokines, adhesion molecules and the infiltration of leukocytes. Role of complement in heart and liver transplant rejection. Indications for cardiac transplantation in infants and children are mainly dilated cardiomyopathy and structural heart disease. The majority of liver transplants are performed in children with biliary atresia; metaobolic liver diseases that result in cirrhosis, such as alpha-1-antitrypsin deficiency and Wilson's disease, are also common indications. The current supply of organs for children is insufficient to meet the need; improving the survival of transplanted organs would significantly reduce donor shortage. We are investigating the role of complement in donor brain death and ischemia and reperfusion injury, risk factors associated with graft survival. We have shown that complement activation is mediated by naturally occurring antibodies that bind to host tissue following brain death and ischemia/reperfusion, and have characterized interactions between complement activation products and other mediators of inflammation and injury. This work is being done in collaboration with other MUSC investigators and investigators at the University of Colorado, Walter Reed Institute and Harvard. Development of novel compliment inhibitors as therapeutic agents. Inhibiting the complement system has been shown to be an effective therapy in animal models of disease (including all of the diseases and transplant conditions listed above). However, complement activation is also important for defense against infection and for keeping the immune system balanced. Thus, systemic and complete complement inhibition may have serious undesirable side effects, particularly for patients who are already immuno-compromised. We are investigating strategies to target complement inhibitors to sites of complement activation and disease. Strategies under investigation involve linking complement inhibitors to fragments of receptors that bind deposited complement (sites of complement activation), and to antibody fragments that bind organ/tissue-specific or inflammation-specific antigens. We have shown that some of these targeting strategies enhance the effectiveness of complement inhibition by more than 10-fold and, furthermore, do not suppress host resistance to infection (unlike their untargeted counterparts). Efforts are currently in process to bring these agents to clinical trials. Some of this work is being performed in collaboration with a biotechnology company that has licensed the technology from MUSC. In summary, investigators in the DCRI Childhood Rheumatic Diseases Program are actively pursuing studies from the bench to the bedside to understand the genetic and environmental causes of these inflammatory diseases, as well as participating in clinical trials of new treatments for these diseases. New collaborations with other investigators in the DCRI have allowed us to expand our efforts into other diseases impacting the health of children. Figure 1: Inhibition of complement ameliorates arthritis in a mouse model. In this model, mice are injected with collagen and develop autoimmune polyarthritis with significant similarities to human rheumatoid arthritis and juvenile inflammatory arthritis. A single injection of CR2-Crry, a targeted complement inhibitor that we have developed, significantly reduced clinical disease activity (upper panel) and joint injury (lower panel). Untreated (control) mice are shown in a. and c. CR2-Crry treated mice shown in b. and d. Note normal joint architecture in d. The inhibitor was injected at onset of clinical disease.
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