{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:31:22Z","timestamp":1780669882125,"version":"3.54.1"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T00:00:00Z","timestamp":1697760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003896","name":"Henry M. Jackson Foundation","doi-asserted-by":"publisher","award":["W81XWH-18-2-0040"],"award-info":[{"award-number":["W81XWH-18-2-0040"]}],"id":[{"id":"10.13039\/100003896","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements. The TLR4 agonist LPS administered i.v. induced very transient immune activation, including TNF-\u03b1 expression and monocyte activation. The TLR7\/8 agonist 2BXy elicited more persistent cytokine expression, including type I IFN, IL-1RA, and the proinflammatory IL-6, along with T cell and monocyte activation. Delivery of 2BXy i.v. and i.m. achieved comparable immune activation, which increased with escalating dose. Finally, i.v. bacillus Calmette\u2013Gu\u00e9rin (BCG) vaccination (which activates multiple TLRs, especially TLR2\/4) elicited the most pronounced and persistent innate and adaptive immune response, including strong induction of IFN-\u03b3, IL-6, and IL-1RA. Strikingly, monocyte, T cell, and NK cell expression of the proliferation marker Ki67 increased dramatically following BCG vaccination. This aligned with a large increase in total and BCG-specific cells measured in the lung. Principal component analysis of the combined cytokine expression and cellular activation responses separated animals by treatment group, indicating distinct immune activation profiles induced by each agent. In sum, we report safe, effective doses and routes of administration for three TLR agonists that exhibit discrete immunomodulatory properties in primates and may be leveraged in future immunotherapeutic strategies.<\/jats:p>","DOI":"10.4049\/jimmunol.2300424","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T13:06:34Z","timestamp":1697807194000},"page":"1643-1655","source":"Crossref","is-referenced-by-count":4,"title":["Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques"],"prefix":"10.1093","volume":"211","author":[{"given":"Hannah A D","family":"King","sequence":"first","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"},{"name":"U.S. Military HIV Research Program, Walter Reed Army Institute of Research , Silver Spring, MD"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supriya","family":"Pokkali","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dohoon","family":"Kim","sequence":"additional","affiliation":[{"name":"U.S. Military HIV Research Program, Walter Reed Army Institute of Research , Silver Spring, MD"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0640-3395","authenticated-orcid":false,"given":"Daniel","family":"Brammer","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaimei","family":"Song","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9175-5534","authenticated-orcid":false,"given":"Elizabeth","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9687-8921","authenticated-orcid":false,"given":"Chelsea","family":"Lehman","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John-Paul","family":"Todd","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4418-6495","authenticated-orcid":false,"given":"Kathryn E","family":"Foulds","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0035-2802","authenticated-orcid":false,"given":"Patricia A","family":"Darrah","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Seder","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-499X","authenticated-orcid":false,"given":"Diane L","family":"Bolton","sequence":"additional","affiliation":[{"name":"U.S. Military HIV Research Program, Walter Reed Army Institute of Research , Silver Spring, MD"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Roederer","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, National Institutes of Health , Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,20]]},"reference":[{"key":"2025020406202540500_r1","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.7150\/jca.24577","article-title":"Current status and future directions of cancer immunotherapy","volume":"9","author":"Zhang","year":"2018","journal-title":"J. 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