Abstract
Multiple immune parameters such as frequencies of autoreactive CD4+, CD8+ T-cells and CD4+CD25+Foxp3+ T-cells have been explored as biomarkers in human T1D. However, intra-individual temporal variation of these parameters has not been assessed systematically over time. We determined the variation in each of these parameters in a cohort of T1D and healthy donors (HDs), at monthly intervals for one year. Despite low intra- and inter-assay co-efficient of variation (CV), mean CVs for each of the immune parameters were 119.1% for CD4+ T-cell-derived IFN-γ, 50.44% for autoreactive CD8+ T-cells, and 31.24% for CD4+CD25+Foxp3+ T-cells. Further, both HDs and T1D donors had similar CVs. The variation neither correlated with BMI, age, disease duration or insulin usage, nor were there detectable cyclical patterns of variation. However, averaging results from multiple visits for an individual provided a better estimate of the CV between visits. Based on our data we predict that by averaging values from three visits a treatment effect on these parameters with a 50% effect size could be detected with the same power using 1.8–4-fold fewer patients within a trial compared to using values from a single visit. Thus, our present data contribute to a more robust, accurate endpoint design for future clinical trials in T1D and aid in the identification of truly efficacious therapies.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive T-cells destroy insulin-producing beta cells in the pancreatic islets
While epidemiological studies have shown that incidence of T1D is rising rapidly [9,10,11], T1D patients remain without a therapeutic agent that can alter the underlying disease process
A majority of the healthy donors (HDs) cohort was female and younger; in contrast, the T1D cohort contained a similar number of males and females
Summary
Type 1 diabetes (T1D) is an autoimmune disease in which autoreactive T-cells destroy insulin-producing beta cells in the pancreatic islets (reviewed in 1,2). Immunological biomarkers [13] that could reliably demonstrate a therapeutic effect on the immune system can help identify patients that would respond to a therapy, and in doing so, reduce the time required to run these clinical trials and be more cost effective. Towards this goal, several immune parameters, including CD4+CD25+Foxp3+ T-cells [14,15,16] and autoreactive CD4+ [17] and CD8+ T-cells [18] have been explored as possible biomarkers. Data was analyzed to determine overall longitudinal variation in each of these parameters, the effect of such variation on patient numbers required to see significant changes, and associations between immune and clinical parameters
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