{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:56:04Z","timestamp":1790283364070,"version":"4.1.0"},"reference-count":56,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T00:00:00Z","timestamp":1692662400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Low-dose anti\u2013thymocyte globulin (ATG) transiently preserves C-peptide and lowers HbA1c in individuals with recent-onset type 1 diabetes (T1D); however, the mechanisms of action and features of the response remain unclear. Here, we characterized the post hoc immunological outcomes of ATG administration and their potential use as biomarkers of metabolic response to therapy (i.e., improved preservation of endogenous insulin production).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      We assessed gene and protein expression, targeted gene methylation, and cytokine concentrations in peripheral blood following treatment with ATG (\n                      <jats:italic>n<\/jats:italic>\n                      = 29), ATG plus granulocyte colony\u2013stimulating factor (ATG\/G-CSF,\n                      <jats:italic>n<\/jats:italic>\n                      = 28), or placebo (\n                      <jats:italic>n<\/jats:italic>\n                      = 31).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Treatment with low-dose ATG preserved regulatory T cells (Tregs), as measured by stable methylation of\n                      <jats:italic>FOXP3<\/jats:italic>\n                      Treg-specific demethylation region (\n                      <jats:italic>TSDR<\/jats:italic>\n                      ) and increased proportions of CD4\n                      <jats:sup>+<\/jats:sup>\n                      FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      Tregs (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001) identified by flow cytometry. While treatment effects were consistent across participants, not all maintained C-peptide. Responders exhibited a transient rise in IL-6, IP-10, and TNF-\u03b1 (\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.05 for all) 2 weeks after treatment and a durable CD4\n                      <jats:sup>+<\/jats:sup>\n                      exhaustion phenotype (increased PD-1\n                      <jats:sup>+<\/jats:sup>\n                      KLRG1\n                      <jats:sup>+<\/jats:sup>\n                      CD57\n                      <jats:sup>\u2013<\/jats:sup>\n                      on CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells [\n                      <jats:italic>P<\/jats:italic>\n                      = 0.011] and PD1\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      Temra MFI [\n                      <jats:italic>P<\/jats:italic>\n                      &lt; 0.001] at 12 weeks, following ATG and ATG\/G-CSF, respectively). ATG nonresponders displayed higher proportions of senescent T cells (at baseline and after treatment) and increased methylation of\n                      <jats:italic>EOMES<\/jats:italic>\n                      (i.e., less expression of this exhaustion marker).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      Altogether in these exploratory analyses, Th1 inflammation-associated serum and CD4\n                      <jats:sup>+<\/jats:sup>\n                      exhaustion transcript and cellular phenotyping profiles may be useful for identifying signatures of clinical response to ATG in T1D.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT02215200.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>The Leona M. and Harry B. Helmsley Charitable Trust (2019PG-T1D011), the NIH (R01 DK106191 Supplement, K08 DK128628), NIH TrialNet (U01 DK085461), and the NIH NIAID (P01 AI042288).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.161812","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T12:00:36Z","timestamp":1689076836000},"source":"Crossref","is-referenced-by-count":42,"title":["Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5144-7836","authenticated-orcid":true,"given":"Laura M.","family":"Jacobsen","sequence":"first","affiliation":[{"name":"Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA."},{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Diggins","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Blanchfield","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"McNichols","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0607-2238","authenticated-orcid":true,"given":"Daniel J.","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9800-9251","authenticated-orcid":true,"given":"Jason","family":"Brant","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3039-3004","authenticated-orcid":true,"given":"Xiaoru","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA."},{"name":"Department of Biostatistics, University of Florida, Gainesville, Florida, 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