The aims of the center are to expand the basic and clinical research directed at the development of new therapeutic approaches and testing them in clinical trials, to establish a multidisciplinary lupus center and to coordinate all these activities under one roof. Establishing a center for the study of SLE will hopefully open new therapeutic directions that will lead to improvement in the medical care of patients suffering from SLE and related autoimmune diseases.

Introduction
Systemic lupus erythematosus (SLE) is a chronic rheumatic disease that usually affects young women, and is associated with wide-ranging clinical manifestations. The etiology of lupus is not well understood. It is thought to result from a disorder in the immune regulation system whereby an immune response is induced against host antigens and subsequently leads to inflammation and irreversible damage to target organs. It usually pursues a chronic course and may lead to death due to lesions affecting the kidneys, the central nervous system and other vital organs.

The current therapy of lupus is based on corticosteroids, which suppress the over-reactive immune system. This therapy, however, is not specific and its inevitable side effects may themselves be fatal. In recent years, extensive clinical and research activities are being conducted in the clinical immunology and rheumatology units of the Department of Medicine at the Hadassah Medical center.

The outpatient lupus clinic takes care of more than 500 patients with lupus and allied autoimmune disorders and serves as a referral center for patients from other medical centers in Israel. Six senior staff members, experienced in clinical immunology and rheumatology, as well as residents, fellows and specialized nurses take part in the care of these patients. Due to the wide range of clinical problems, physicians from other medical disciplines contribute to the treatment program. Patients who need hospitalization for evaluation, diagnosis and treatment of their disease are hospitalized in the Department of Medicine, where a team of senior physicians provides a high standard of medical care.

The diagnostic service is provided by the laboratory of clinical immunology,. This laboratory provides the work-up necessary for the diagnosis ad evaluation of autoimmune diseases. In addition to the routine tests done in other laboratories, our lab performs detailed analysis of autoantibodies which is not available in other centers in Israel.

Research in lupus, arthritis and autoimmune disorders is conducted by two research teams, directed by Prof. Yaakov Naparstek and by Prof. Dan Eilat. Both teams are involved in the study of the etiology and pathogenesis of autoimmunity with special emphasis on the development of specific therapeutic modalities. The research work involves modern techniques of cellular and humoral immunology, as well as molecular biology. The work done by these teams contributed significantly to the understanding of autoimmunity and has laid the basis for new experimental therapeutic approaches.
In order to improve the medical care of lupus patients and extend the basic and clinical research, we feel it is valuable to establish a center for the study of lupus and related autoimmune disorders that will centralize and coordinate all these activities.

The aims of the center would be:

• To further investigate disease mechanisms in order to develop more effective therapy, and to test these new modalities in clinical trials.
• To establish a multidisciplinary outpatient clinic.
• To establish a center for training of physicians and scientists that are involved in the treatment of lupus.

The main goal of the center for the study of SLE and autoimmune disorders is to improve the quality of care of these patients. This will be achieved by expanding the research activities, by establishing a multidisciplinary outpatient clinic and by training more physicians who are involved in the treatment of these diseases.

Research

The following directions will be addressed.

1. Deciphering the etiopathogenesis of SLE.
   1. Identification of the self-antigens that are recognized by the pathogenic autoreactive lymphocytes.
   2. Isolation of the pathogenic clones of lymphocytes. Analysis of their genes and of the autoantibodies produced by them.
      
      
2. New therapeutic approaches.
   1. Production of "tailor-made" drugs that will block specifically the binding of the pathogenic antibodies to the target organs.
   2. Ex-vivo immunoabsorption of the pathogenic autoantibodies by plasmapheresis through solid-phase columns carrying the target antigens.
      

A multidisciplinary lupus center
SLE is associated with a variety of clinical manifestations: persistent fever, an erythematosus rash, polyarthritis, pleuritis, pericarditis, anemia and aberrations in renal, neurologic and cardiac functions. The treatment of SLE therefore involves the combined efforts of specialists in various medical fields: rheumatologists, clinical immunologists, nephrologists, dermatologists, psychologists, orthopedic surgeons, physical therapists and many others. In order to coordinate the therapy program, we aim to establish a multidisciplinary outpatient center that will enable us to use efficiently the contribution of all these specialists and thus improve the quality of the medical care of the patients.

Training
The multiplicity of the clinical symptoms of SLE requires both profound understanding of basic immunology as well as clinical expertise in a large number of medical disciplines. We intend to establish a training center in which physicians from other departments who are involved in the treatment of lupus patients will be able to learn the complexity of the disease. We hope that physicians who are trained in our center will eventually become a part of the multidisciplinary team that will take care of these patients.

Funding
In order to achieve the goals outlined in the proposal, we need financial support that will enable us to expand the laboratory space and our clinical and research activities. In order to achieve the goals of this Center, the estimated budget is $1,500,000 over a period of two years.

a. Space
The space currently allocated for the activities of the unit is extremely small. Four physicians and scientists, 4 Ph.D. students and 3 technicians perform the clinical and research laboratory work in an area of approximately 75 square metes. Our goal is to obtain more space which would provide us with sufficient room for diagnostic, as well as research activities. The addition of 150 square meters will enable us to have the facilities for modern research projects and teaching activities.

b. Personnel
Financial support from Israeli sources has been rather limited due to the economic situation in Israel. We were fortunate enough to be able to fund our research projects by grants from European and American scientific agencies. Although this enabled us so far to carry out successfully our projects, those grants have to be renewed on an annual or biannual basis and they cannot secure positions for senior scientists or research assistants. In order to train physicians in the treatment of the disease we need a position for one fellow in clinical immunology. Until now we have paid for this position from various grants when we had this sort of money. It is, however, very difficult to get money for a clinical position (even more difficult than getting a grant for a research project). A constant position for a clinical fellow is therefore needed for the center. To better conduct the clinical activities in the multidisciplinary outpatient clinic, the clinical trials and the research projects, we also need an administrator who will be responsible for the coordination of these activities. We therefore wish to establish an endowment fund that will enable us to add to our staff an additional clinical fellow, senior scientist, a research assistant and an administrator.

Studies in SLE -Ongoing Research and Future Prospects
The research teams in the Hadassah Medical Center that are involved in the study of autoimmune rheumatic diseases are concentrating their efforts in the study of SLE. The researchers try to clarify the basic derangements that lead to the development of SLE, to identify the pathogenic clones of the immune system, and to develop more specific therapeutic approaches that will affect only the pathogenic mechanism and leave the rest of the organism intact.

The etiology of SLE is not well understood. The disease is thought to result from a disorder in immune regulation whereby the autoimmune reactions induced against host antigens subsequently lead to inflammation and damage to the target organs. The damage to the target organs results from the interaction of the pathogenic lupus autoantibodies with their self-target antigen.

During the past several years, researchers at the unit have been studying SLE in both patients suffering from the disease and in experimental models-focusing on the two "players" that are involved in disease induction: the pathogenic autoantibodies and their tissue target antigen. The researchers believe that precise identification of these components and deciphering of their interaction will enable us to develop more specific therapeutic modalities for patients with SLE.

Their research endeavors focus on several main directions:

A research group of the unit, led by the principal investigator Prof. Dan Eilat, is analyzing the binding regions of the anti-DNA antibodies derived from mice that develop spontaneous SLE. Using protein sequencing and molecular biology techniques, they have identified the structure of the genes that encode the antigen-binding site of several lupus antibodies. These findings may lead to therapy directed specifically at the pathogenic antibodies. Indeed, one of their major interests is to study the mechanisms of tissue injury in SLE. In particular, they have been interested in the immunochemical differences between pathogenic and non-pathogenic anti-DNA autoantibodies. Recently, they have discovered an interesting cross-reaction of pathogenic anti-DNA antibodies (but not of non-pathogenic antibodies) with a cellular protein that is prevalent in certain glomerular components, such as epithelial foot processes and mesangial cells.
This group has also produced by gene targeting "knock-in" transgenic mice that express a simple anti-DNA heavy chain or one heavy/light chain combination. These mice serve as excellent tools for studying tolerance mechanisms in autoimmune mice, and the fate of antibody producing B cells in normal and lupus-prone mice.

SLE is known to affect the blood vessels in many vital organs, including the brain and kidney. Indeed, renal complications are the most frequent cause of death from this condition. Recently, various lines of evidence indicate that the previously suggested mechanism based on the formation of DNA-anti-DNA immune complexes can not explain the specific effects of the disease in various organs, including the kidney. A research groups at the unit led by Prof. Naparstek has been investigating the hypothesis that the antibodies against DNA may bind directly to kidney and blood vessel tissue, thereby inducing glomerulonephritis.
The researchers have found that the pathogenic lupus antibodies bind to a small peptide (termed TV 5100), located in the extracellular matrix of the renal and vascular basement membranes. This finding was confirmed in various models of lupus mice including transgenic, congenic and SCID mice and in antibodies derived from lupus patients.
Based on this finding the researchers have generated a panel of "tailor made" molecules that can interfere with the reaction between the pathogenic antibodies and their target tissue peptide and have used these molecules successfully to treat the disease in lupus mice.
The next step was to study the potential use of these molecules for treatment of human disease. The researchers have bound the peptide to a solid-phase columns and succeeded to "clean" sera derived from lupus patients from the pathogenic antibodies by absorbing it on this device.
The present aim of this group is to develop this specific absorption device for clinical use for the treatment of lupus patients by specific immuno-absorption plasmapheresis.