Background: Lupus nephritis is a leading cause of morbidity and mortality for lupus patients. Although current immunosuppressive regimens have dramatically improved its prognosis they are not uniformly effective and are associated with significant toxicities. Elucidation of the pathogenesis of lupus nephritis is of paramount importance to improve the currently available therapeutic regimens. Production of pathogenic autoantibodies by B lymphocytes and formation of immune complexes are the hallmarks of the disease. Although absolute B lymphocyte numbers are low or normal in patients with SLE, they have an activated phenotype. Little is known, however about the role of different subsets of B cells and their relation to disease activity. Autoantibody production is antigen driven and depends on activated T cells. Recently it has been recognized that a subset of T cells the so-called regulatory T lymphocytes play an important role in the suppression of ongoing immune activation. It is conceivable that abnormalities in regulatory T cell may contribute to autoimmune diseases. The most effective immunosuppressive treatments for lupus nephritis are based on cyclophosphamide. A significant proportion of patients, especially African-Americans, do not respond appropriately to this drug, however. The toxicities associated with cyclophosphamide can be severe, therefore distinguishing between these two groups before starting therapy would be highly desirable. Genetic polymorphisms in several key enzymes of cyclophosphamide metabolism have been described recently and identifying those that may be related to the different responses of individual patients would be helpful in making treatment decisions and spare the risk of toxicity from patients who are unlikely to respond to cyclophosphamide. Objectives: 1. To analyze B lymphocyte subsets and identify subsets that may be related to changes in disease activity 2. To analyze the function of regulatory T lymphocytes 3. To examine the feasibility of PET scanning to detect activated lymphoid organs 4. To study the pharmacogenomics of cyclophosphamide therapy. Results: 1. B cell subsets in SLE. In collaboration with the Autoimmunity Branch, we characterized the abnormal B cell pattern of lupus patients. We identified B cell subsets that are not normally found in the peripheral blood some of which seem to correlate with disease activity. The functional characterization of these cells is in progress. 2. Regulatory T cells: our preliminary data indicate that Treg are abnormal in number, phenotype and function in patients with active SLE that could contribute to the pathogenesis of disease flares in these patients. 3. FDG-PET in SLE: Lupus patients had higher uptake in their lymphnodes compared to controls, regardless of disease activity, suggesting that the immune system is activated even during periods of clinical quiescence. An increased activity of the thymus was observed in active lupus patient compared to inactive patients, suggesting that the thymus may play an important role during active disease. 4. Pharmacogenomics: We completed a study analyzing the correlation between genetic polymorphisms of hepatic cytochrome P450 enzymes and response to cyclophosphamide. We found a strong correlation between long-term renal outcomes and the presence of certain genetic phenotypes as well as a correlation between premature ovarian failure (the most common long-term side-effect of this treatment) and polymorphisms in these genes. Lay Summary: Involvement of the kidneys (nephritis) is the main cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). In this so called autoimmune disease, the body turns against itself producing antibodies directed to molecules found in body tissues (antigens). In lupus nephritis, complexes of antigens with antibodies (immune complexes) deposit in the kidney and cause inflammation leading to kidney failure if left unchecked. Antibodies are produced by a certain type of immune cells called B lymphocytes. Although patients with active SLE usually have lower number of B lymphocytes in their blood they are more active then in healthy people. We have identified some abnormal B lymphocytes in the blood of patients with active lupus patients that are not found in healthy people. Other immune cells called regulatory T lymphocytes, may be important in suppressing autoimmunity; therefore we initiated studies examining the function of these regulatory cells in lupus. We also explored the genetic basis of why some lupus patients respond well to cyclophosphamide (the most effective therapy for lupus nephritis) while others do not. We found that variation in certain genes that effect the activation of cyclophosphamide is associated with differences in the rate of response and side-effect associated with this therapy. Progress since last year 1. We studied the peripheral B lymphocytes of patients with active lupus nephritis and identified several subsets that are not found in the peripheral blood of healthy people, some of which correlate with disease activity. 2. Preliminary data suggest that impaired regulatory T cell function in patients with active lupus. 3. FDG-PET identified an increased activity of peripheral lymph-nodes in both active and inactive lupus patients. Active, but not inactive patient also had an increase in thymic activity. 4. We have shown that genetic polymorphisms of selected hepatic cytochrome P450 enzymes are associated with a higher risk of end-stage renal disease but a lower risk of premature ovarian failure. Goals for next year Continue to study the correlation between disease activity and B cell phenotypes. Define regulatory T cell abnormalities further. Start new therapeutic protocols in lupus nephritis and in SLE, in general. Planned studies include protocols using an anti-IL6 receptor monoclonal antibody, a B-cell depleting monoclonal antibody as an addition to usual treatment and establish an autologous stem cell therapy program.
Showing the most recent 10 out of 21 publications
