Reduction in CD4 central memory T-cell subset in costimulation modulator abatacept-treated patients with recent-onset type 1 diabetes is associated with slower C-peptide decline

Abstract

We previously reported that continuous 24-month costimulation blockade by abatacept significantly slows the 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-naive, memory and activated subsets, myeloid and plasmacytoid dendritic cells, monocytes, B lymphocytes, CD4(+)CD25(high) regulatory T cells, and invariant NK T cells) by flow cytometry at baseline and 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 the peripheral contraction of CM CD4 T cells and the expansion of naive (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 the diagnosis of type 1 diabetes and that costimulation blockade may exert its beneficial therapeutic effect via modulation of this subset.

Trial registration: ClinicalTrials.gov NCT00505375.

Figure 1

Percentage change from baseline of CD4 T-cell subsets identified as representing naive (A) and CM (B) cell populations, as well as the naive cell/CM cell ratio (C) and Treg populations (D). Closed circles represent abatacept-treated subjects, and open circles represent placebo-treated subjects; symbols represent the median, and error bars represent 95% CIs. P values and dashed lines indicate that the two groups differ significantly over the time points indicated.

Figure 2

Representative flow cytomteric analyses of gated CD4 T cell–naive (CD45R0⁻CD62L⁺) and CM T cell (CD45R0⁺CD62L⁺) subpopulations at different time points during the study in which patients were receiving maintenance therapy (abatacept or placebo) when tested at 3, 6, 12, and 24 months, at which point treatment ceased. Numbers in quadrants are the percentages of each subset. A: Lysed whole-blood staining of a type 1 diabetes patient from the placebo group. There is no notable change in the percentage of CM cells (top right quadrant) or the percentage of naive cells (bottom right quadrant). B: A patient in the abatacept-treated arm of the study, in whom there is marked change in the proportion of circulating CM (reduced) and naive (increased) CD4 T cells, respectively. FITC, fluorescein isothiocyanate.

Figure 3

Log change in C-peptide 2 years after baseline vs. log change in the percentage of CD4⁺ CM T cells at 1 year. Filled circles represent abatacept-treated subjects, and open circles represent placebo-treated subjects. Lines represent regression estimates from the fitted statistical model: abatacept, solid line; placebo, dashed line.