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. The long-term risk-benefit ratio of immunosuppressive therapies can only be evaluated in long-term follow up studies. Renal flares may contribute significantly to progression to end-stage renal disease, however, there are very few data in the literature analyzing their frequency and prognostic significance. Elucidation of the pathogenesis of lupus nephritis is of paramount importance to improve the currently available therapeutic regimens. Production of pathogenic autoantibodies to a limited number of nuclear and cytoplasmic antigens and formation of immune complexes are the hallmarks of the disease. Autoantibody production is antigen driven and T cell dependent. Studies in animals and humans have demonstrated the essential role of interactions involving the CD40 - CD40L pair of molecules in this process. CD40-ligand (CD40L) is transiently expressed primarily on the surface of activated CD4+ T cells. Interaction of CD40L with its receptor CD40, which is constitutively expressed by B cells and macrophages, is involved in both humoral and cellular immune responses. CD40L is expressed on <1% of human CD4+ T cells from normal controls, but on >17% of CD4+ T cells from active SLE patients. Persistent expression of CD40L on T cells of lupus patients has been reported. Upregulation of CD40 expression has also been observed in renal biopsy specimens from patients with proliferative but not membranous lupus nephritis. Antibodies to CD40L ameliorate nephritis in several animal models of lupus. Tissue injury in lupus is mediated predominantly by deposition of immune complexes (IC) in tissues such as kidneys. Most pathogenic immunecomplexes contain DNA and anti-DNA antibodies. It has long been postulated that bacterial DNA contributes to induction or perpetuation of SLE. Bacterial DNA contains CpG motifs that activate lymphocytes, macrophages and NK cells. CpG motifs derived from bacterial DNA can boost the production of autoantibodies in animal models and CpG rich DNA is present in the anti-dsDNA/DNA complexes found in lupus sera. Other factors, such as infiltrating monocytes may also play an important role in the initiation and progression of kidney diseases, since immunecomplex depostion in itself does not result in tissue injury. Objectives: 1. To examine the therapeutic activity of anti-CD40L therapy in patients with lupus nephritis and to examine the impact of anti-CD40L therapy on B and T cells, and autoantibody production. 2. To further delineate the role of interaction between macrophages and resident renal cells (mesangial and tubular epithelial cells) in the pathogenesis of lupus nephritis. 3. To study the natural history of lupus nephritis treated with different immunosuppressive regimens and to examine their long-term toxicity and efficacy. 4. To describe the prevalence of flares, determine their impact on long-term renal outcome and identify prognostic factors of flares in patients with lupus nephritis with at least partial response to immunosuppressive therapies. 5. To analyze the response of lupus patients to oligodeoxynucleotides containing CpG-motifs. Results: 1. Anti-CD40L Therapy. A multicenter study sponsored by Biogen, Inc. has been initiated with NIH as one of the 3 leading centers. We have evaluated over 30 patients and have enrolled 6 patients in this study before enrollment was stopped due to an unexpected numbers of serious adverse events associated with this molecule. In addition to clinical parameters, immune responses before and after treatment were analyzed in detail, in collaboration with the Autoimmunity Branch of NIAMS. 2. Role of macrophages and the interaction between macrophages and resident renal cells in lupus nephritis. In contrast to previous findings, suggesting defective monocyte function, we have shown that monocytes from lupus patients are capable to produce increased amounts of TNF-a and IL-12, a cytokine known to promote Th1 immune responses. We also demonstrated that, in co-culture experiments, activated monocytes from these patients are fully capable of inducing glomerular injury, by inducing IL-6 and MCP-1 production of mesangial cells. 3. The natural history of lupus nephritis treated with different immunosuppressive regimens: long-term toxicity and efficacy. We have finished a long-term follow-up study of patients participating in our most recent randomized trial of immunosuppressive drugs. We found, that after an average follow-up of 11 years, pulse cyclophosphamide continues to show superior efficacy over pulse methylprednisolone alone in the treatment of lupus nephritis. The combination of pulse cyclophosphamide and pulse methylprednisolone appears to provide an additional advantage over pulse cyclophosphamide alone while not conferring additional risks of adverse events. 4. We have analyzed the predictors of renal flares/exacerbations and their impact on long-term renal survival in a cohort of patients with proliferative lupus nephritis, who achieved at least partial response with immunosuppressive therapy. Flares were classified as proteinuric or nephritic. Flares were predicted by undetectable C4 levels at the time of response and African-American ethnicity. Progression to end-stage renal disease was associated with creatinine >2mg/dl at the time of response, severe nephritic flares, a higher chronicity and activity index at study entry and not achieving a complete response. As expected, patients who fulfilled criteria for stabilization only without achieving complete response, had higher likelihood of severe nephritic flares and end-stage renal disease. 5. Response of lupus patients to oligodeoxynucleotides containing CpG-motifs: Peripheral blood mononuclear cells from healthy individuals can recognize and respond differently to two discrete types of CpG motifs. In collaboration with the FDA, we compared the response to CpG motifs of PBMC from lupus patients and normal controls. Preliminary results show that PBMC from SLE patients mount a significantly reduced response to both types of CpG oligodeoxynucleotides. The underlying cause and importance of this observation is currently evaluated. 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. The role of certain inflammatory cells, such as lymphocytes, has been described previously but little is known about the role of monocytes (a different type of inflammatory cell) in this process. Blocking the action of a molecule called CD40 ligand in animals interferes with the inflammation and may prevent serious kidney damage. Our studies are aimed at a) identifying the therapeutic potential of a molecule blocking CD40 ligand in patients with lupus and b) to evaluate the role of monocytes in kidney injury. To this end, we participated in a clinical trial evaluating the effect of an anti-CD40 ligand antibody and compared the function of monocytes in patients with lupus nephritis. Moreover, we grow cells from kidney biopsies of patients and examine their functions in the test tube. Finally, we monitor a group of over 150 lupus patients that have participated in studies on the treatment of lupus nephritis in an effort to better understand the course of the disease and the long-term s
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