The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

Sernoskie, Samantha Christine; Jee, Alison; Uetrecht, Jack

doi:10.1124/pharmrev.120.000090

Cited by 23 publications

(31 citation statements)

References 467 publications

(515 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neutrophil increases have been demonstrated in patients beginning clozapine treatment ( Blackman et al , 2021 ; Sernoskie et al , 2021 ) and in our rat model ( Abdel-Wahab and Metwally, 2014 ; Lobach and Uetrecht, 2014b ; Ng et al , 2014 ; Wasti et al , 2006 ). To examine the induction of this immune response in the rat model, changes in leukocyte populations were evaluated over 24 h following a single clozapine dose (30 mg/kg).…”

Section: Resultsmentioning

confidence: 51%

“…Several groups have reported clozapine-mediated hepatic ( Jia et al , 2014 ; Zlatkovic et al , 2014 ), cardiac ( Abdel-Wahab and Metwally, 2015 ; Mohammed et al , 2020 ; Nikolic-Kokic et al , 2018 ; Wang et al , 2008 ), splenic ( Abdelrahman et al , 2014 ; Mohammed et al , 2020 ), and other ( Lobach and Uetrecht, 2014b ; Ng et al , 2014 ; Wasti et al , 2006 ) immune changes but, aside from our group, these effects have been reported following several weeks, not hours, of clozapine administration (reviewed in Sernoskie et al [2021 ]). The differences in inflammatory mediator changes observed in the spleen and bone marrow in the present study not only underscore the complexity of the immune response to clozapine, but the observed increases in IL-1β and other proinflammatory mediators support further investigation of organ-specific inflammasome activation in this response in vivo .…”

Section: Discussionmentioning

confidence: 68%

“…IDIAG is believed to be an adaptive immune-mediated reaction associated with specific HLA haplotypes ( Chowdhury et al , 2011 ; Legge and Walters, 2019 ) and T cell receptors ( Ogese et al , 2020 ). However, induction of this adaptive response must be preceded by innate immune activation; an early response that does not appear to be idiosyncratic ( Sernoskie et al , 2021 ). Previously, we began characterizing the innate response to clozapine using a rat model ( Lobach and Uetrecht, 2014b ; Ng et al , 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…We postulate that this innate response is a necessary, but alone insufficient, step in the mechanism that, in some patients, precedes IDIAG: a reaction that appears to be mediated by the adaptive immune system ( Johnston and Uetrecht, 2015 ). This innate response is required for activation of antigen presenting cells but, presumably, will not result in IDIAG without T cell activation and clonal expansion ( Sernoskie et al , 2021 ), necessitating HLA molecules that can present clozapine-modified peptides to cognate T cell receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Mandatory hematological monitoring has demonstrated that most patients develop a transient innate immune response within the first weeks of clozapine treatment, evidenced by paradoxical neutrophilia and increased levels of circulating proinflammatory mediators, including C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α ( Blackman et al , 2021 ; Sernoskie et al , 2021 ). Previous investigations have demonstrated that clozapine induces a similar acute increase in circulating neutrophils in rats ( Lobach and Uetrecht, 2014b ; Ng et al , 2014 ; Wasti et al , 2006 ) and rabbits ( Iverson et al , 2010 ).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Sernoskie

Lobach

Kato

et al. 2021

Toxicological Sciences

Self Cite

View full text Add to dashboard Cite

Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and non-differentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1β release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague-Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1β, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1β production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of idiosyncratic drug-induced agranulocytosis, enabling safer, more frequent use of clozapine in patients.

show abstract

Section: Resultsmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Sernoskie

Lobach

Kato

et al. 2021

Toxicological Sciences

Self Cite

View full text Add to dashboard Cite

show abstract

Unveiling the therapeutic promise of natural products in alleviating drug‐induced liver injury: Present advancements and future prospects

Singh,

Khan,

Siddique

2023

Phytotherapy Research

View full text Add to dashboard Cite

Drug‐induced liver injury (DILI) refers to adverse reactions to small chemical compounds, biological agents, and medical products. These reactions can manifest as acute or chronic damage to the liver. From 1997 to 2016, eight drugs, including troglitazone, nefazodone, and lumiracoxib, were removed from the market due to their liver‐damaging effects, which can cause diseases. We aimed to review the recent research on natural products and their bioactive components as hepatoprotective agents in mitigating DILI. Recent articles were fetched via searching the PubMed, PMC, Google Scholar, and Web of Science electronic databases from 2010 to January 2023 using relevant keywords such as “natural products,” “acetaminophen,” “antibiotics,” “paracetamol,” “DILI,” “hepatoprotective,” “drug‐induced liver injury,” “liver failure,” and “mitigation.” The studies reveal that the antituberculosis drug (acetaminophen) is the most frequent cause of DILI, and natural products have been largely explored in alleviating acetaminophen‐induced liver injury. They exert significant hepatoprotective effects by preventing mitochondrial dysfunction and inflammation, inhibiting oxidative/nitrative stress, and macromolecular damage. Due to the bioavailability and dietary nature, using natural products alone or as an adjuvant with existing drugs is promising. To advance DILI management, it is crucial to conduct well‐designed randomized clinical trials to evaluate natural products' efficacy and develop new molecules clinically. However, natural products are a promising solution for remedying drug‐induced hepatotoxicity and lowering the risk of DILI.

show abstract

Idiosyncratic Adverse Drug Reactions

Mak,

Uetrecht

2024

Reference Module in Biomedical Sciences

View full text Add to dashboard Cite

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

Cited by 23 publications

References 467 publications

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

Unveiling the therapeutic promise of natural products in alleviating drug‐induced liver injury: Present advancements and future prospects

Idiosyncratic Adverse Drug Reactions

Contact Info

Product

Resources

About