Use of the brown Norway rat model of D-penicillamine-induced autoimmunity to study idiosyncratic drug reactions, in particular immune tolerance.
Published: 2004
Language: eng
Number of pages: 160
Description: Idiosyncratic drug reactions (IDRs), among the most serious adverse drug reactions, are a major clinical problem accounting for significant morbidity and mortality. The unpredictable nature and low incidence (&lt;1% for a given drug) of IDRs limits human studies and necessitates the use of animal models. The Brown Norway (BN) rat model of D-penicillamine-induced autoimmunity is useful to study IDRs.To explain the observation that the vast majority of patients do not develop IDRs, it has been proposed that the dominant response to drugs in most patients is immune tolerance. Often, the incidence of IDRs is decreased if patients are given low starting doses. Likewise, low dose pretreatment with D-penicillamine prevents autoimmunity in the BN rat. Evidence that low dose tolerance to D-penicillamine is immune-mediated was found as splenocytes from low dose pretreated rats secrete the regulatory cytokines, TGF-beta and IL-10, and transfer tolerance to naive recipients.Although the disease induced by D-penicillamine in rats and humans clearly involves a systemic autoimmune response, the roles of T cells and other immune cells have not been defined. As antigen presenting cells (APCs) with phagocytic capability, macrophages are key immune cells with the potential to initiate immune responses and mediate tissue damage. Evidence that macrophages, acting as APCs, could be involved in the pathogenesis of D-penicillamine autoimmunity was found by correlating the incidence of disease with the degree of splenic infiltration by B7-expressing macrophages. As well, the incidence of autoimmunity appeared to be decreased in macrophage-depleted rats. Short term treatment with tacrolimus, a T cell inhibitor, not only prevented autoimmune disease, but also reversed symptoms of disease despite ongoing treatment with D-penicillamine, and prevented disease upon re-challenge. Such findings may prove to be clinically useful in managing potentially fatal IDRs.A risk factor of IDRs in humans was also identified in rats. Often the onset of D-penicillamine-induced autoimmunity occurs after months to years of treatment and coincides with activation of the immune system by viral illnesses or UV exposure. Poly I:C, an immunostimulant, dose-dependently prevented the induction of tolerance and reversed established tolerance to D-penicillamine in the BN rat.
Notes: Adviser: Jack Vetrecht.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2361.