{
  "abstract": "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—including graft-versus-host disease and lupus—where IL-2 driven expansion correlates with improvements in some clinical markers of disease activity.\n\nAutoimmunity 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.\n\nSix months after alemtuzumab treatment, the frequency of patient-derived naïve CD4+ Teffs expressing high-affinity IL-2 receptors increased from 30.11% ± 5.09% to 72.88% ± 5.57%, 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.\n\nGuided 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 × 106 IU/m2 twice a week), was well tolerated and safe, but unexpectedly failed to expand Tregs.\n\nWe 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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "Zoya G Georgieva",
      "orcid": "0000-0002-9531-8884"
    },
    {
      "name": "Sarah K Howlett"
    },
    {
      "name": "Daniel B Rainbow"
    },
    {
      "name": "Valerie Coppard"
    },
    {
      "name": "Lou Ellis"
    },
    {
      "name": "Lorna B Jarvis"
    },
    {
      "name": "Evangelia Williams"
    },
    {
      "name": "Jennie H M Yang"
    },
    {
      "name": "Bo Sun",
      "orcid": "0000-0002-5507-6657"
    },
    {
      "name": "Timothy Tree"
    },
    {
      "name": "Alasdair J Coles",
      "orcid": "0000-0003-4738-0760"
    },
    {
      "name": "Linda S Wicker"
    },
    {
      "name": "Joanne L Jones",
      "orcid": "0000-0003-4974-1371"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8meehp39h9ec0.bib",
  "cited_by": 1,
  "doi": "10.1093/brain/awag171",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13730587/",
  "id": "8meehp39h9ec0",
  "issns": [
    "0006-8950",
    "1460-2156"
  ],
  "landing_url": "https://doi.org/10.1093/brain/awag171",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/MED00310"
    ],
    [
      "heading",
      "AcademicSubjects/SCI01870"
    ],
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2728|Multiple Sclerosis Research Studies"
    ]
  ],
  "openalex": "W7160991655",
  "pdf_url": null,
  "pmcid": "PMC13730587",
  "pmid": "42126089",
  "published": "2026-05-13",
  "publisher": "Oxford University Press",
  "ris": "https://research.draconitic.com/paper/8meehp39h9ec0.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:23:06Z",
      "native_id": "PMC13730587",
      "source": "pmc",
      "url": "https://doi.org/10.1093/brain/awag171"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Multiple Sclerosis Research Studies",
      "subfield": "neurology"
    }
  ],
  "title": "Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis",
  "title_text": "Low-dose IL-2 fails to expand Tregs after alemtuzumab: insight into impaired immune tolerance in multiple sclerosis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:23:06Z",
  "url": "https://research.draconitic.com/paper/8meehp39h9ec0",
  "venue": "Brain",
  "versions": []
}