{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T04:48:27Z","timestamp":1766983707843,"version":"3.37.3"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000023","name":"Government of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000023","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Genome Canada and Ontario Genomics","award":["OGI-099"],"award-info":[{"award-number":["OGI-099"]}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["178188"],"award-info":[{"award-number":["178188"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013739","name":"Pfizer Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013739","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ontario Graduate Scholarship"},{"name":"Glaxo-Wellcome Sunnybrook Drug Safety Clinic Graduate Student"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity\/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1\u2212\/\u2212 mice are more susceptible to drug-induced liver injury, but PD-1\u2212\/\u2212 mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m\/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m\/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m\/m rats developed more severe liver injury than PD-1\u2212\/\u2212 mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae058","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T16:06:51Z","timestamp":1716221211000},"page":"382-393","source":"Crossref","is-referenced-by-count":2,"title":["The use of PD-1 functional knockout rats to study idiosyncratic adverse reactions to nevirapine"],"prefix":"10.1093","volume":"200","author":[{"given":"Tiffany","family":"Cho","sequence":"first","affiliation":[{"name":"Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto , Toronto, Ontario M5S 3M2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, University of Guelph , Guelph, Ontario N1G 2W1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey T","family":"Henderson","sequence":"additional","affiliation":[{"name":"Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto , Toronto, Ontario M5S 3M2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack","family":"Uetrecht","sequence":"additional","affiliation":[{"name":"Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto , Toronto, Ontario M5S 3M2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"2024072915003119900_kfae058-B1","doi-asserted-by":"crossref","first-page":"4749","DOI":"10.1073\/pnas.1718217115","article-title":"Role of PD-1 during effector CD8 T cell differentiation","volume":"115","author":"Ahn","year":"2018","journal-title":"Proc. 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