Immune-mediated toxicity

Traditionally immune mediated toxicity has been suspected on clinical grounds such as the presence of fever rasly an eosinophil response, a delay between exposure to the toxin and the onset of clinical symptoms, and the accelerated recurrence of symptoms and signs of toxicity after readministration... 

Mechanisms of drug-induced kidney disease include immune-mediated toxicities (e.g., glomerulonephritis and allergic interstitial nephritis) and nonimmunologic-mediated toxicities which effect specialized characteristics of normal renal physiology. 

In a study of the mechanism whereby BordeteUa pertussis vaccine increased acute ozone toxicity in rats, Thompson ascribed the effects to /3-adrenergic blockade, and not to an immune-mediated response. It was further noted that both atropine and reserpine reduced mortality, whidi suggested that the acute lethal effects of ozone were due to shock and circulatory collapse, rather than pulmonary edema. 

This statement is somewhat at odds with the conventional view that idiosyncratic toxicology is dose-size independent. Idiosyncratic reactions are thought to result from an immune-mediated cell injury triggered by previous contact with the drug. The toxicity may appear after several asymptomatic administrations of the com-... 

Table 17.1 lists non-oncology compounds from diverse therapeutic, chemical, pharmacological areas and structures that induce clinical hematotoxicity. This demonstrates that bone marrow toxicity is not restricted to a small number of pharmacological or structural classes, thereby making it more difficult to understand specific mechanisms of toxicity. However, there are three classes of mechanisms of hematotoxicity, including antiproliferative, immune-mediated and other. Immune-mediated hematotoxicity and other indirect toxicities (e.g., a decrease of erythropoietin in kidney, leading to an impeded red cell production in the bone marrow) are not discussed in detail in this chapter as it requires involvement of the immune system or remote interactions and in vitro profiling assays have not been developed to detect these mechanisms. 

In addition to oxygen free radicals, other compounds such a clozapine, olanzapine and procainamide induce reactive intermediates [8, 9]. Clozapine and olanzapine bioactivation is thought to occur through a nitrenium ion [20] however clozapine but not olanzapine induce toxicity to neutrophils. This can lead to an immune-mediated depletion of neutrophils and their precursors (CFU-GM) [21]. Also, nonsteroidal antiinflammatory drugs (NSAIDs) have pro-oxidant radicals that when metabolized could cause oxidative stress [22]. 

Immune-mediated mechanisms of clozapine-induced agranulocytosis have been reviewed in the context of agranulocytosis in a 46-year-old woman (140). Immune and toxic mechanisms have also been explored in patients taking clozapine, three who developed agranulocytosis, seven who developed neutropenia, and five who were asymptomatic. There was no evidence of antineutrophil antibodies in the blood of patients shortly after an episode of clozapine-induced agranulocytosis, and an antibody mechanism... 

Ah-receptor mediated toxicity resulted in wide range of biological responses, including alterations in metabolic pathways, body weight loss, thymic atrophy, impaired immune responses, hepatotoxicity, chloracne and related skin lesions, developmental and reproductive effects, and neoplasia. 

Complementary to vascular compromise and mechanically impaired axoplasmic flow, additional pathogenic mechanisms (Figures 30.3 30.4) that underlie glaucomatous optic neuropathy include excitotoxic damage from excessive retinal glutamate, peroxynitrite toxicity from increased nitric oxide synthase activity, immune-mediated nerve damage, and oxidative stress (Naskar and Dreyer, 2001). 

Many reactions to beta-lactam antibiotics are clearly not immune mediated. These include bleeding disorders, neurotoxicity, and most cases of diarrhea. In addition, many reactions, the pathogenesis of which is still being discussed, clearly depend on the daily and the cumulative dose of beta-lactam antibiotics and hence the duration of treatment. Although the rare, but well-understood, immune hemolysis after penicillin is seen mostly with high-dose and long-term treatment, dose dependency and time dependency point to direct toxicity rather than to immunological mechanisms. Indeed, direct toxic effects of beta-lactam antibiotics on eukaryotic cells and specific interactions with receptor proteins and enzymes have been shown (4) and may underlie particular reactions. 

Interferon alfa was also suspected to be involved in one case of biopsy-proven bronchiolitis obliterans-organizing pneumonia (41). Clinical symptoms of pneumonitis appeared 3-12 weeks after the onset of interferon alfa therapy, and after withdrawal of treatment they usually completely resolved, either spontaneously or after a short course of glucocorticoid treatment. Immune-mediated pulmonary toxicity involving the activation of T cells was considered as a likely mechanism. The uncommon features of bronchiolitis obliterans-organizing pneumonia have been reported in three other patients who received interferon alfa together with ribavirin or cytosine arabino-side (42,43). 

The kinetics of the hemotoxic effects of interferon alfa have been studied in 76 patients with chronic hepatitis C (210). There were significant falls in white blood ceU count and platelet count within 12 hours after the first injection, and a second fall in platelet count after 2 weeks, but not further thereafter. This rapid time-course suggests that liver or spleen sequestration of blood cells, rather than direct bone marrow suppression or immune-mediated hematological toxicity, is the most likely explanation for this acute hemotoxic effect, which does not preclude continuation of treatment. 

Numerous investigators have reported and reviewed the chnical application of monoclonal antibodies in various areas, including organ transplantation, neoplastic diseases, severe sepsis, and chronic inflammatory diseases. Collectively, these antibodies generally did not produce major adverse effects. The rapid development of antibodies against murine monoclonal antibodies is one of the most important clinical hmitations to their therapeutic use, but the development of humanized (chimeric human/ murine) monoclonal antibodies has improved their safety. Monoclonal antibodies have also been used in non-immune mediated diseases, such as cancer, septic shock, reperfusion, and as antiplatelet drugs. Treatment of neoplastic diseases with monoclonal antibodies is theoretically attractive. Unfortunately none of the monoclonal antibodies available at present has been demonstrated to be strictly tumor-specific, and binding of antibody to normal cells has been shown to be the major unknown factor for toxicity (6). 

Agranulocytosis (probably due to toxicity rather than hypersusceptibility) can be caused by sulindac (13), as can bone marrow aplasia (14) and severe thrombocytopenia (15,16), which may be the consequence of autoimmune platelet destruction in the presence of sulindac or its metabolite (SEDA-7, 109). Immune-mediated hemolytic anemia with a positive direct antiglobulin test has been reported (SEDA-18,103). 

Because of the rare and unpredictable nature of hepatobihary reactions to terbinafine, the mechanism of hepatotoxicity has been hypothesized to be either immunological or metabolically mediated. A potentially toxic reactive metabolite of terbinafine, 7,7-dimethylhept-2-ene-4-jmal (TBF-A), the A-dealkylation product of terbinafine, has been identified in vitro (43). The authors speculated that this allylic aldehyde metabolite, formed by hver enzymes and conjugated with glutathione, would be transported across the canalicular membrane of hepatocytes and concentrated in the bile. The reactive monoglutathione conjugate could bind to hepatobiliary proteins and cause direct toxicity. Alternatively, it could modify canahcular proteins and lead to an immune-mediated reaction, causing cholestatic dysfunction. 

A direct toxic effect of vancomycin and/or an immune-mediated mechanism (antineutrophil antibodies, sensitized lymphocjrtes) have been discussed. 

Studies of xenobiotic-induced immune dysregulation in animal models. Hydralazine and procainamide-induced autoimmunity HgClj and gold salt-induced autoimmunity The impact of genetic studies in our understanding of immunological-mediated toxic-induced renal disease ... 

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