{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T03:29:47Z","timestamp":1792553387821,"version":"4.5.0"},"reference-count":62,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T00:00:00Z","timestamp":1666569600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovative Medicines Initiative 2 Joint Undertaking","award":["777357"],"award-info":[{"award-number":["777357"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,24]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>\n                      Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under \u201csub-immunogenic\u201d conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II\n                      <jats:sub>259-273<\/jats:sub>\n                      (CII) and NF-\u03baB inhibitor 1,25-dihydroxycholecalciferol.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin\n                      <jats:sub>59-71<\/jats:sub>\n                      \u2013specific (Cit-Vim\u2013specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01\n                      <jats:sup>+<\/jats:sup>\n                      or *01:01\n                      <jats:sup>+<\/jats:sup>\n                      ACPA\n                      <jats:sup>+<\/jats:sup>\n                      RA patients on methotrexate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim\u2013specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1\n                      <jats:sup>+<\/jats:sup>\n                      T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181\u2013treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim\u2013specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7\n                      <jats:sup>+<\/jats:sup>\n                      and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      The safety and immunomodulatory activity of low\/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA\n                      <jats:sup>+<\/jats:sup>\n                      RA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union\u2019s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.160964","type":"journal-article","created":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T14:00:56Z","timestamp":1666533656000},"source":"Crossref","is-referenced-by-count":56,"title":["Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide\/calcitriol liposomes in ACPA+ rheumatoid arthritis"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6077-8816","authenticated-orcid":true,"given":"Amee","family":"Sonigra","sequence":"first","affiliation":[{"name":"Department of Rheumatology, 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