Subcutaneous Abatacept in New Onset Type 1 Diabetes: Clinical and Immunological Effects

Abstract

Abatacept is a CTLA4-Ig fusion protein that blocks CD80/CD86-dependent T-cell co-stimulation. When administered, Abatacept limits, to a variable degree, loss of stimulated C-peptide secretion in patients with newly-diagnosed type 1 diabetes (T1D), while reducing both circulating memory CD4⁺ T-cells and T follicular helper (Tfh) cells; however, its precise mechanism of action is not known. To investigate this effect, we studied 12 patients, using multi-parameter flow cytometry, who each self-administered Abatacept in subcutaneous formulation for 6 months within 100 days of diagnosis. Abatacept treatment impacted the CD4⁺ T cell memory compartment, inducing a reduction in T-effector cells across both conventional (Tconv) and regulatory (Treg) sub-populations. A reduction in activated Tfh cells (CXCR5⁺PD1⁺ICOS⁺), previously described with intravenous therapy, was replicated and extended. An integrated baseline immunological phenotype predicted Abatacept-induced preservation of C-peptide.

Keywords: Abatacept; diabetes; immunotherapy.

FIGURE 1

Percentage change from baseline of AUC c‐peptide/AUC glucose ratios for Abatacept‐treated patients (n = 11) and control patients (n = 8) (A) and individual values for treated patients (B) and controls (C). ** = p < 0.01.

FIGURE 2

Spaghetti plots of naïve/memory cells within the Tconv, Treg and CD8 subpopulations.

FIGURE 3

Spaghetti plots of aTfh and aTfr within Tconv and Treg subpopulations.

FIGURE 4

Percentage contribution of individual principal components to intergroup variance.

FIGURE 5

Hierarchical clustering dendrogram demonstrating separation of responders (blue) and non‐responders (green) with even distribution of controls (red).