Tolerance Induced by Low Dose d-Penicillamine in the Brown Norway Rat Model of Drug-Induced Autoimmunity Is Immune-Mediated

Most patients taking drugs associated with idiosyncratic drug reactions tolerate the drug and do not develop adverse reactions. Understanding the mechanism of tolerance to drugs is important as it could provide insight into why some patients develop idiosyncratic reactions and others do not. The Brown Norway rat model of d-penicillamine-induced autoimmunity was used as a model of idiosyncratic drug-induced autoimmunity. Two weeks of low dose (5 mg/day) d-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally seen in 60−80% of rats treated with high dose (20 mg/day) d-penicillamine. Low dose pretreatment also prevented the increase in IgE and IL-4 mRNA characteristic of the response to high dose d-penicillamine. Experiments were conducted to determine whether low dose tolerance is metabolic or immunological. It was found that low dose tolerance possesses key characteristics of immune-mediated tolerance: memory, splenocytes that adoptively transfer tolerance, and regulatory cytokine production. To provide an understanding of the factors that can prevent or reverse established tolerance, the conditions for inducing and maintaining tolerance were investigated. Tolerance induction was investigated by manipulating the immune system during the period of low dose exposure. The induction of tolerance was partially prevented by depleting the macrophage subset of antigen presenting cells with clodronate-filled liposomes or by inhibiting T cells with tacrolimus during the period of low dose exposure. As well, the induction of tolerance was completely prevented by repeatedly stimulating the immune system throughout the period of low dose pretreatment with poly I:C. To investigate the permanence of tolerance, the immune system was stimulated after tolerance induction in an attempt to break tolerance. Both LPS and poly I:C reversed tolerance in a dose-dependent manner. These results demonstrate that immune tolerance to d-penicillamine autoimmunity can be induced by short-term low dose pretreatment.