Purine synthesis inhibition in experimental lupus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that mainly affects women. The effect of the immune modulating drug mycophenolate mofetil (MMF) on experimental SLE was investigated. Mycophenolic acid (MPA), the active metabolite of MMF, inhibits inosine 5 -monophosphate dehydrogenase (IMPDH), an important enzyme in the de novo synthesis of the purine guanine. The clinical and histopathological outcome of MMF administration to SLE-prone MRLlpr/lpr mice in vivo was assessed. In addition, the immunomodulating properties of MPA in vitro on splenocytes from MRLlpr/lpr mice as well as on the macrophage cell line IC-21 were studied.Treatment of MRLlpr/lpr mice with MMF prolonged survival and diminished kidney damage as demonstrated by reduced albuminuria, hematuria and immune complex depositions in glomeruli. Perivascular cell infiltrates in kidneys and salivary glands were also reduced following MMF treatment. MMF reduced lymphoproliferation, the production of IgG anti-dsDNA antibodies and the populations of double-negative T cells as well as immunoglobulin-producing B cells. All the clinical effects of MMF were comparable with those achieved with cyclophosphamide treatment. In vitro, mitogen-stimulated splenocytes from MMF-treated mice displayed increased proliferative responses and augmented IFN-g and IL-10 production. In vitro treatment of MRLlpr/lpr spleen cells with MPA resulted in decreased mitogen-induced proliferative responses and the decreased production of IFN-g, IL-10, immunoglobulins and anti-DNA antibodies. Furthermore, exposure of the macrophage cell line IC-21 to MPA decreased mitogen-induced proliferation and the production of NO2-, IL-1b, and TNF-a. Addition of guanosine in vitro totally abrogated the action of the drug, proving that guanine-nucleotide depletion is the mechanism whereby MPA exerts its immunomodulating effects. It is concluded that the immunomodulating effects of MMF are to a large extent mediated by purine synthesis inhibition in lymphocytes and in macrophages. In addition, the results indicate that MMF can be considered as a potentially efficacious treatment for SLE patients with glomerulonephritis.