Reduction in CD4 Central Memory T-cell subset in Co-Stimulation Modulator Abatacept-Treated Patients with Recent-Onset Type 1 Diabetes is Associated with Slower C-Peptide Decline. Diabetes. May 16, 2014. [Epub ahead of print] Orban T1, Beam CA2, Xu P2, Moore K3, Jiang Q3, Deng J3, Muller S2, Gottlieb P4, Spain L5, Peakman M6; The Type 1 Diabetes TrialNet Abatacept Study Group.
1Joslin Diabetes Center, Boston, MA; 2Division of Informatics and Biostatistics, Department of Pediatrics, University of South Florida, Tampa, FL; 3David. H. Murdock Research Institute, Kannapolis, NC.; 4University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora CO.; 5NIDDK/NIH, Bethesda, M.; 6Peter Gorer Department of Immunobiology, School of Medicine, King’s College London, UK.
We previously reported that continuous 24-month co-stimulation blockade by abatacept significantly slows decline of β-cell function after diagnosis of Type 1 diabetes. In a mechanistic extension of that study, we evaluated peripheral blood immune cell subsets (CD4, CD8 naïve, memory and activated subsets, myeloid and plasmacytoid dendritic cells, monocytes, B lymphocytes, CD4+CD25high regulatory T-cells and invariant NK T-cells) by flow cytometry at baseline, 3, 6, 12, 24 and 30 months after treatment initiation to discover biomarkers of therapeutic effect. Using multivariable analysis and lagging of longitudinally measured variables we made the novel observation in the placebo group that an increase in central memory (CM) CD4 T-cells (CD4+CD45R0+CD62L+) during a preceding visit was significantly associated with C-peptide decline at the subsequent visit. These changes were significantly affected by abatacept treatment, which drove peripheral contraction of CM CD4 T-cells and expansion of naïve (CD45R0-CD62L+) CD4 T-cells in association with a significantly slower rate of C-peptide decline. The findings show that the quantification of CM CD4 T-cells can provide a surrogate immune marker for C-peptide decline after diagnosis of Type 1 diabetes, and that co-stimulation blockade may exert its beneficial therapeutic effect via modulation of this subset.
© 2014 by the American Diabetes Association. PMID: 24834977 [PubMed – as supplied by publisher]