Biology subjects

Wicker, L. S.

Publications and source records attributed to Wicker, L. S..

3 recordsLinked to original sources

bioRxiv2017

Targeting regulatory T cells with Interleukin-2 treatment in type 1 diabetes: a response-adaptive, non-randomised, open-label trial of repeat doses of Aldesleukin (DILfrequency)

BackgroundType 1 diabetes (T1D) results from loss of immune regulation leading to the development of autoimmunity to pancreatic beta-cells, involving autoreactive T effector cells (Teffs). Regulatory T cells (Tregs), that prevent autoimmunity, require Interleukin-2 (IL-2) for maintenance of immunosuppressive functions and, alterations in the IL-2 pathway predispose to T1D. Using an adaptive trial design we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of autoreactive Teffs.\n\nMethodsDILfrequency is a single-center, non-randomised, open-label, response-adaptive study of participants aged 18 to 70 years with T1D. The initial learning phase allocated 12 participants to six different predefined dose-frequency regimens. Then, three cohorts of 8 participants were sequentially allocated dose-frequencies, based on repeated interim analyses of all accumulated trial data. The co-primary endpoints were percentage change in Tregs, Teffs and, CD25 ( subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. Trial registration ISRCTN40319192 and ClinicalTrials.gov (NCT02265809).\n\nFindings115 participants were assessed between November 17th 2014 and May 22nd 2016, 38 participants were enrolled with 36 completing treatment. The optimal regimen to maintain a steady state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 x 106 IU/m2 (95% CI (-0.007 to 0.485)) every 3 days (1.3 to 4.4). Tregs and CD25 were dose-frequency responsive, while Teffs were not. The commonest adverse event was injection site reaction (464/694 events), with a single participant developing transient eosinophilia at the highest dose (0.47 x 106 IU/m2).\n\nInterpretationThis response-adaptive trial defined a well-tolerated aldesleukin regimen that specifically induces Treg expansion that can now be trialled to treat T1D.\n\nFundingSir Jules Thorn Trust, Wellcome, JDRF, SNSF, NIHR

clinical trials↗

bioRxiv2017

Cells With Treg-Specific FOXP3 Demethylation But Low CD25 Are Prevalent In Autoimmunity

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3 that is highly enriched in HELIOS+ cells, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+; P = 1.3 x 10-9) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 x 10-18), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells are highly correlated (P = 1.2 x 10-19) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.\n\nHighlights- FOXP3+ compartment within CD127lowCD25low T cells is expanded in autoimmune patients.\n\n- Increased numbers of CD25lowFOXP3+ T cells are a circulating marker of autoimmunity.\n\n- CD25lowFOXP3+ HELIOS+ T cells are fully demethylated at the FOXP3 TSDR.\n\n- CD25lowFOXP3+ T cells could represent a terminal stage of regulatory T cells.

immunology↗

bioRxiv2017

Chromosome contacts in activated T cells identify autoimmune disease-candidate genes

BackgroundAutoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes.\n\nResultsWithin four hours, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach.\n\nConclusionsOur systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.

genomics↗