Investigation of the Involvement of Macrophages and T Cells in D-Penicillamine-Induced Autoimmunity in the Brown Norway Rat

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Abstract
The initiating events in drug-induced autoimmunity are poorly understood and difficult to study. We examined the role of macrophages and T-cells in the Brown Norway rat model of D-penicillamine-induced autoimmunity. When activated, macrophages can act as both antigen presenting cells, initiating immune responses, and as phagocytic cells mediating systemic tissue damage. We found that B7+ macrophages are the major antigen-presenting cell type infiltrating the spleen and caecum early in the response to Dpenicillamine. As well, the increase in splenic B7+ macrophages correlates with the incidence of autoimmune disease. Treatments that increase the incidence of disease accentuate the increase in splenic B7+ macrophages, and treatments that prevent disease also prevent the increase in B7+ macrophages. In vivo depletion of macrophages appeared to decrease, but not totally prevent, autoimmune disease. The role of T-cells in D-penicillamine-induced autoimmunity was also examined using the T-cell inhibitor tacrolimus. Short-term treatment with tacrolimus not only prevented disease onset but also reversed ongoing disease and prevented disease relapse upon re-challenge with D-penicillamine. The results of this study indicate that both macrophages and T-cells could be important immune cell types involved in D-penicillamine-induced autoimmunity. Furthermore, the effects of tacrolimus in this model suggest that short-term tacrolimus treatment may be an effective way to prevent or treat IDRs in high-risk patients.