B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes
Peter S. Linsley, Carla J. Greenbaum, Cate Speake, S. Alice Long, Matthew J. Dufort
Peter S. Linsley, Carla J. Greenbaum, Cate Speake, S. Alice Long, Matthew J. Dufort
View: Text | PDF
Research Article Therapeutics

B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes

Abstract

Costimulatory interactions control T cell activation at sites of activated antigen-presenting cells, including B cells. Blockade of the CD28/CD80/CD86 costimulatory axis with CTLA4Ig (abatacept) is widely used to treat certain autoimmune diseases. While transiently effective in subjects with new-onset type 1 diabetes (T1D), abatacept did not induce long-lasting immune tolerance. To elucidate mechanisms limiting immune tolerance in T1D, we performed unbiased analysis of whole blood transcriptomes and targeted measurements of cell subset levels in subjects from a clinical trial of abatacept in new-onset T1D. We showed that individual subjects displayed age-related immune phenotypes (“immunotypes”) at baseline, characterized by elevated levels of B cells or neutrophils, that accompanied rapid or slow progression, respectively, in both abatacept- and placebo-treated groups. A more pronounced immunotype was exhibited by a subset of subjects showing poor response (resistance) to abatacept. This resistance immunotype was characterized by a transient increase in activated B cells (one of the cell types that binds abatacept), reprogrammed costimulatory ligand gene expression, and reduced inhibition of anti-insulin antibodies. Our findings identify immunotypes in T1D subjects that are linked to the rate of disease progression, both in placebo- and abatacept-treated subjects. Furthermore, our results suggest therapeutic approaches to restore immune tolerance in T1D.

Authors

Peter S. Linsley, Carla J. Greenbaum, Cate Speake, S. Alice Long, Matthew J. Dufort

×

Figure 2

Gene level analysis reveals elevated B cell genes in treated NR subjects and elevated neutrophil cell genes in R subjects.

Options: View larger image (or click on image) Download as PowerPoint
Gene level analysis reveals elevated B cell genes in treated NR subjects...
(A) Volcano plots of individual gene expression differences between abatacept- and placebo-treated subjects calculated using a linear model implemented in limma-voom (22) (gene expression ~ treatment model). Horizontal line indicates FDR = 0.2. Red indicates B cell genes (CD19.mod); blue indicates neutrophil genes (MPO.mod). Sample numbers were as in Figure 1A. (B) Individual gene expression differences between R and NR abatacept-treated subjects (gene expression ~ group model). (C) B cell genes were enriched in abatacept-treated NR subjects, neutrophil genes in R subjects. Shown are plots of expression levels of selected B cell and neutrophil genes at the day 84 visit. Two-sided Wilcoxon P values for group comparisons are indicated. P values are presented without multiple testing correction. (D) Altered expression of T cell costimulatory ligands in R and NR subjects. Shown are plots of expression levels of selected T cell costimulatory ligand molecules. Molecules whose expression was not different between the R and NR groups, and molecules whose expression differed significantly between R and NR. Two-sided Wilcoxon P values for group comparisons are indicated. P values are presented without multiple testing correction. *****P < 1 × 10–5; ****P > 1 × 10–5 and < 1 × 10–4; ***P > 1 × 10–4 and < 1 × 10–3; **P > 1 × 10–3 and < 1 × 10–2; *P > 1 × 10–2 and < 0.05.