Single and combined effects of the vitamin D analogue KH1060 and cyclosporin A on mercuric-chloride-induced autoimmune disease in the BN rat

Abstract

SUMMARY: Mercuric chloride induces in BN rats a self-limiting systemic autoimmune disease characterized by proliferation of autoreactive CD4+ T lymphocytes, polyclonal activation of B lymphocytes, and the development of an anti-glomerular basement membrane (GBM) nephritis with concomitant nephrotic range protcinuria. We have used this model of autoimmune disease to test the immunosuppressive ability of a novel vitamin D3 analogue KH 1060. This compound prevents autoimmune manifestations including proteinuria. scrum IgE, and serum anti-laminin antibodies in a dose-dependent manner, as does cyclosporin A (CyA). When dosages of KH 1060 capable of partial reduction of proteinuria without causing significant hypercalcaemia are combined with small dosages of CyA also capable of partial prevention of protcinuria, an additive effect is seen, leading to complete prevention of proteinuria and substantial reductions in serum IgE and anti-laminin levels. Possible mechanisms of action are discussed and it is suggested that KH1060 could prove useful as an immunosuppressive agent in the treatment of autoimmune diseases.