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Biology subjects

Mander, A. P.

Publications and source records attributed to Mander, A. P..

2 recordsLinked to original sources

Frequent Monitoring of C-peptide Levels in Newly Diagnosed Type 1 Subjects Using Dried Blood Spots Collected at Home

ObjectiveTo evaluate a novel approach to measure {beta}-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBS)\n\nPatientsThirty-two children, aged 7-17 years, recently diagnosed with type 1 diabetes.\n\nDesignMixed-meal-tolerance-test (MMTT) within 6 and again 12 months after diagnosis with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home.\n\nResultsDBS and plasma C-peptide levels (n=115) correlated strongly (r=0{middle dot}91; p<0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance permitting accurate description of changes over time. The correlation of the C-peptide slope over time assessed by repeated home DBS versus area under the curve during the two MMTTs was r=0{middle dot}73; p<0.001. Mixed models showed that a 1-month increase of diabetes duration was associated with 17 pmol/l decline in fasting DBS C-peptide, whereas increases of 1 mmol/l in glucose, 1 year older age-at-diagnosis and 100 pmol/l higher baseline plasma C-peptide were associated with 18, 17 and 61 pmol/l higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration.\n\nConclusionOur approach permitted frequent assessment of C-peptide, making it feasible to monitor {beta}-cell function at home. Evaluation of changes in the slope of C-peptide using this method may permit short-term evaluation of promising interventions.

biochemistry

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