Nase I in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects over one million people in the United States alone [140]. SLE is characterized by the presence of antinuclear antibodies (ANA) directed against naked DNA and nucleosomes. The resulting immune complexes are deposited in the kidney, joints, and blood vessels, causing glomerulonephritis, arthritis, and vasculitis, respectively. The underlying cause of this disease is linked with deficiencies in serum amyloid P (SAP) component [141], certain complement proteins [142,143], and a decreased serum DNase I activity [144-146]. These proteins are all known to be involved in the clearance of apoptotic bodies in extracellular fluids like serum. The decreased activity of DNase I in SLE has originally been associated with increased concentrations of actin in serum of SLE patients [146]. Later on, however, a mutation of the gene encoding DNase I [147] and antiDNase I antibodies were found in certain SLE patients [148,149]. Considering the pathophysiology of SLE, degradation of extracellular DNA, nucleosomes, or DNA-containing immune complexes by DNase I may reduce the production of ANA and the deposition of immune complexes. In the 1960s, Lachmann [150] reported that subcutaneous (s.c.) bovine DNase I in SLE patients resulted in a reduction of ANA and improvements in systemic symptoms. However, after 4-6 weeks of treatment, the positive effects were lost due to the development of antibodies against bovine DNase I. The availability of rhDNase I and recombinant murine (rMu) DNase I in the 1990s led to several trials with DNase I in mice and humans. Intraperitoneal injection of rMuDNase I in young SLE mice delayed the development of antiDNA antibodies (Figure 5.8) and lupus symptoms by about one month [151,152]. In one placebo-controlled study, rMuDNase I even reduced nephritis in older SLE mice with established renal disease [151]. A phase I clinical trial in humans with SLE showed that rhDNase I is well tolerated in SLE patients after a single intravenous dose of up to 125 ^g/kg, and five consecutive daily s.c. administrations of up to 125 ^g/kg rhDNase I [153]. Antibodies against rhDNase I were dsDNA

ssDNA

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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