Cyclin kinase inhibitors and interferons in lupus

Many investigators have directly examined the role of deleted/blocked or overexpressed immune-related genes in lupus background mice. The effects of such manipulations have provided important insights into the crucial molecules and pathways involved in this disease and into the development of new therapies. We report here on the effects of two classes of genes: cyclin-dependent kinase inhibitor p21, and interferons (IFNs).

A characteristic feature of lupus in humans and mice is the accumulation of activated/memory T cells and B cells. These G1-arrested cells express high levels of p21, are resistant to proliferation and apoptosis, and express high levels of proinflammatory cytokines. We hypothesized that accumulation of these cells results from repetitive engagements by self-molecules in vivo, and that deletion of p21 may lead to their reduction. Indeed, lupus-prone BXSB mice lacking p21 have enhanced T-cell and B-cell proliferation but, importantly, have increased apoptosis, resulting in a net reduction of activated/memory cells and marked inhibition of disease. Increased apoptosis of p21-deleted cells is mediated by engagement of both the extrinsic (Fas/FasL) and intrinsic (Bcl2) related pathways. Modulation of the cell-cycle pathway may be a novel approach to reduce activated/memory-resistant and apoptosis-resistant pathogenic T cells and B cells, and to ameliorate systemic autoimmunity. Another class of molecules to ameliorate lupus is type I and type II IFNs, since considerable evidence exists that these pleiotropic molecules are important effectors in this disease. Our earlier studies showed decreased serologic, cellular and histologic disease characteristics and increased survival of MRL-Faslpr mice deleted of the IFN-γ gene or treated, even at advanced stages, with cDNA encoding IFN-γR-Fc. More recently, we created congenic NZB mice lacking the α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous-deleted mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in several immune cell subsets (including B1 cells) and reduced dendritic cell maturation. The cumulative data indicate that both type I and type II IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.