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

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.

d-Penicillamine-Induced Autoimmunity: Relationship to Macrophage Activation

“…The fact that penicillamine caused rapid macrophage activation while the onset of autoimmunity occurs after about 3 weeks of treatment strongly suggests that macrophages play a role in the initiation of the immune response leading to autoimmunity. This is consistent with our previous study in which significant infiltration of activated macrophages into the cecum was found only 96 h after penicillamine treatment (27).…”

The Role of Host-Generated H2S in Microbial Pathogenesis: New Perspectives on Tuberculosis

“…For instance, treatment of murine RAW264.7 macrophage cells with D -penicillamine activates these cells via direct binding of D -penicillamine to cell-surface aldehydes, resulting in increased production of cytokines TNF-α, IL-6, and IL-23 ( Li and Uetrecht, 2009 ). Likewise, D -penicillamine was shown to activate macrophages and T-cells, undergirding the ability of this compound to induce autoimmunity in Brown Norway rats ( Masson et al., 2004 ). Overall, D -penicillamine inhibits CSE and activates immune cells, in addition to other functions.…”

Drugs and autoimmunity – A contemporary review and mechanistic approach

“…The T cell inhibitor tacrolimus can prevent disease onset, reverse ongoing disease, and prevent disease relapse upon re-exposure to D-penicillamine in this mouse model, emphasizing the importance of a T cell role in the mechanism of disease. Experimental depletion of macrophages significantly decreases the incidence of the disease, so both cell types and probably their interaction are important in inducing drug-related autoimmune disease [30]. Enhanced macrophage activation, and increased expression of allele 3 of the solute carrier family 11 member a1 (SLC11A1), has been shown to be associated with autoimmune disease [31].…”