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Anti-KIR Antibodies Treat Lupus in Mice

Strickland FM, Johnson KJ and Richardson BC

Epigenetically altered T cells cause lupus in genetically predisposed mice, and similar T cells are found in patients with active lupus. More recent reports demonstrate that the epigenetically altered cells comprise a novel CD4+CD28+ T cell subset characterized by co-overexpression of genes normally suppressed by DNA methylation, including those encoding CD11a, CD70, CD40L and the killer cell immunoglobulin-like receptor (KIR) gene family. Inducing a T cell DNA methylation defect in lupus-prone mice causes a similar subset and lupus. Since KIR genes are not expressed by normal T cells, we tested if antibodies to KIR proteins treat lupus in in mice. A cytotoxic antibody to murine KIR proteins was generated and injected into lupus-prone mice with a T cell DNA methylation defect. The antibody prevented the development of glomerulonephritis in the mice. This suggests that anti-KIR antibodies may be useful in the treatment of human lupus, although the long-term safety and efficacy remain to be established.