{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:01:43Z","timestamp":1777914103995,"version":"3.51.4"},"reference-count":45,"publisher":"SAGE Publications","issue":"8","license":[{"start":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T00:00:00Z","timestamp":1606521600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Toxicol Pathol"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:p>Phosphatidylinositol 3-kinases (PI3Ks) regulate intracellular signaling events for multiple cell surface receptors. Phosphatidylinositol 3-kinase \u03b4, 1 of 4 class I PI3K isoforms, is primarily found in leukocytes and regulates immune cell functions. Here, we report changes in the immune and digestive systems that were associated with AMG2519493, a highly selective small-molecule PI3K\u03b4 inhibitor. Following 1- or 3-month oral repeat dosing in the cynomolgus monkey, changes were observed in circulating B cells, lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue, tonsil), and the digestive tract. Decreased circulating B cells and lymphoid cellularity in B cell-rich zones in lymphoid tissues were attributed to the intended pharmacologic activity of AMG2519493. Dose- and duration-dependent digestive system toxicity was characterized by inflammation in the large intestine and secondary opportunistic infections restricted to the digestive tract. Digestive tract changes were associated with moribundity and mortality at high-dose levels, and the effect level decreased with increased duration of exposure. These observations demonstrate the role of PI3K\u03b4 in regulation of the immune system and of host resistance to opportunistic infections of the digestive tract.<\/jats:p>","DOI":"10.1177\/0192623320966238","type":"journal-article","created":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T01:20:10Z","timestamp":1606612810000},"page":"949-964","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Phosphatidylinositol 3-Kinase \u03b4 Inhibitor-Induced Immunomodulation and Secondary Opportunistic Infection in the Cynomolgus Monkey (\n                    <i>Macaca fascicularis<\/i>\n                    )"],"prefix":"10.1177","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-749X","authenticated-orcid":false,"given":"Jonathan A.","family":"Werner","sequence":"first","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsu","family":"Ishida","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Wisler","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"},{"name":"AnaptysBio, San Diego, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Karbowski","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jackson","family":"Kalanzi","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanine","family":"Bussiere","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"Monticello","sequence":"additional","affiliation":[{"name":"Amgen Research, Translational Safety and Bioanalytical Sciences, Thousand Oaks, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2020,11,28]]},"reference":[{"key":"bibr1-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.029"},{"key":"bibr2-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1352-5"},{"key":"bibr3-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2014.12.006"},{"key":"bibr4-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"bibr5-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2882"},{"key":"bibr6-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200838266"},{"key":"bibr7-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2010.10.002"},{"key":"bibr8-0192623320966238","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.02.012"},{"key":"bibr9-0192623320966238","unstructured":"Gilead Sciences I. 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