{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:46:10Z","timestamp":1790682370847,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Pharmaceuticals, Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Antisense oligonucleotides (ASOs) are a new class of single-stranded DNA\u2013based drugs that hold great therapeutic potential. A low incidence of severe, dose-dependent, and reversible thrombocytopenia (TCP) (platelets &amp;lt;\u200950\u2009K\/\u03bcl) has been reported in nonhuman primate (NHP) populations, following treatment of monkeys with 2\u2032-O-methoxy ethyl ASOs (2% to 4% at doses &amp;gt;\u20098 to 10\u2009mg\/kg\/week). The potential mechanisms for this effect were studied using the Mauritian-sourced NHPs, which were shown to be more susceptible to ASO-induced TCP than Asian-sourced animals. In this pilot study, we used a mass cytometry\u2013based intracellular cytokine staining assay, to evaluate the immune-phenotypic and functional changes in cryopreserved PBMCs, collected over 8 time points of ASO therapy (ISIS 405879) from 12 Cambodian and 12 Mauritian monkeys (9 treated and 3 controls). Unsupervised clustering was performed across markers used for cell type identification in the pooled dataset, followed by unsupervised comparison at each time point and then longitudinal analysis. Major immune cell types showed differential abundance between the 2 groups prior to start of ASO therapy. These included IFNg- and TNF-producing polyfunctional effector T cells (CD4+ and CD8+), which were lower, and MIP1b-producing monocytes and DCs, which were higher, in the Mauritian monkeys. Immune populations also changed over the course of this treatment, wherein IL-17- and GM-CSF-producing T cells and IgM-producing B cells increased markedly in Mauritians. Identification of these differentially abundant immune cell subsets in treatment sensitive NHPs could help decipher potential immune mechanisms contributing to severe TCP observed during administration of specific ASO sequences in humans.<\/jats:p>","DOI":"10.1093\/jimmun\/vkae055","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T23:50:21Z","timestamp":1742341821000},"page":"636-650","source":"Crossref","is-referenced-by-count":2,"title":["Cellular immune changes during severe antisense oligonucleotide-associated thrombocytopenia in a nonhuman primate model"],"prefix":"10.1093","volume":"214","author":[{"given":"Sheena","family":"Gupta","sequence":"first","affiliation":[{"name":"Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiang","family":"Shen","sequence":"additional","affiliation":[{"name":"Nonclinical Development, Ionis Pharmaceuticals Inc , Carlsbad, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5817-0369","authenticated-orcid":false,"given":"Scott P","family":"Henry","sequence":"additional","affiliation":[{"name":"Nonclinical Development, Ionis Pharmaceuticals Inc , Carlsbad, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6117-8764","authenticated-orcid":false,"given":"Nima","family":"Aghaeepour","sequence":"additional","affiliation":[{"name":"Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5861-7340","authenticated-orcid":false,"given":"Padmakumar","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Nonclinical Development, Ionis Pharmaceuticals Inc , Carlsbad, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0795-9946","authenticated-orcid":false,"given":"Holden T","family":"Maecker","sequence":"additional","affiliation":[{"name":"Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine , Stanford, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"key":"2025043003515104300_vkae055-B1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1517\/17425255.2013.737320","article-title":"Clinical pharmacokinetics of second-generation antisense oligonucleotides","volume":"9","author":"Yu","year":"2013","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"2025043003515104300_vkae055-B2","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/B978-0-12-803620-4.00028-1","volume-title":". 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