{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T10:25:22Z","timestamp":1786962322893,"version":"build-2736575974"},"reference-count":70,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018956","name":"NIHR Cambridge Biomedical Research Centre","doi-asserted-by":"publisher","award":["BRC-1215-20014"],"award-info":[{"award-number":["BRC-1215-20014"]}],"id":[{"id":"10.13039\/501100018956","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Regulatory T cells (Tregs) are essential to preventing autoimmunity. They depend upon interleukin-2 (IL-2) for optimal function and, due to high expression of the CD25 subunit of the IL-2 receptor, are 10-fold more sensitive to IL-2 than effector T cells (Teffs). Consequently, low-dose IL-2 can be used to expand Tregs preferentially, a therapeutic strategy that has shown promise in a number of autoimmune and inflammatory conditions\u2014including graft-versus-host disease and lupus\u2014where IL-2 driven expansion correlates with improvements in some clinical markers of disease activity.<\/jats:p>\n                  <jats:p>Autoimmunity is a frequent delayed complication of treatment with the lymphocyte-depleting drug alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Here, using in vitro assays, a pre-clinical mouse model and an experimental medicine study, we investigated whether low-dose IL-2 could selectively expand Tregs in alemtuzumab-treated RRMS patients.<\/jats:p>\n                  <jats:p>Six months after alemtuzumab treatment, the frequency of patient-derived na\u00efve CD4+ Teffs expressing high-affinity IL-2 receptors increased from 30.11%\u202f\u00b1\u202f5.09% to 72.88%\u202f\u00b1\u202f5.57%, and the density of receptors per cell increased, rendering them six times more sensitive to IL-2 in vitro, at concentrations that typically favour Tregs. Using a human CD52-expressing transgenic mouse model of alemtuzumab treatment, we found that IL-2 could still preferentially expand Tregs, but only when administered at a later time point, corresponding to more than 6 months post-treatment in patients.<\/jats:p>\n                  <jats:p>Guided by these findings, we evaluated low-dose IL-2 for Treg expansion in a prospective open-label mechanistic study of RRMS patients who had received alemtuzumab more than 6 months previously. IL-2, at a dose and frequency similar to that previously shown to expand Tregs in autoimmune diabetes (0.3 \u00d7 106\u2005IU\/m2 twice a week), was well tolerated and safe, but unexpectedly failed to expand Tregs.<\/jats:p>\n                  <jats:p>We discuss the potential reasons underlying this lack of response, ruling out sIL2RA-related neutralization and instead considering ceiling effects on Treg proliferation, Treg exhaustion and intrinsic Treg dysfunction in MS as possible contributors. Together, our findings demonstrate that low-dose IL-2 alone is not an effective strategy for promoting Treg expansion post-alemtuzumab and is therefore not a viable approach on its own for preventing post-treatment autoimmune complications.<\/jats:p>","DOI":"10.1093\/brain\/awag171","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:22:14Z","timestamp":1778498534000},"source":"Crossref","is-referenced-by-count":0,"title":["Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9531-8884","authenticated-orcid":false,"given":"Zoya G","family":"Georgieva","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah 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B","family":"Jarvis","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, King\u2019s College London , London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie H M","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, King\u2019s College London , London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-6657","authenticated-orcid":false,"given":"Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0QQ 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