B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes
Peter S. Linsley, … , S. Alice Long, Matthew J. Dufort
Peter S. Linsley, … , S. Alice Long, Matthew J. Dufort
Published February 21, 2019
Citation Information: JCI Insight. 2019;4(4):e126136. https://doi.org/10.1172/jci.insight.126136.
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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

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Figure 1

Abatacept treatment triggered transient changes in whole blood gene module expression.

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Abatacept treatment triggered transient changes in whole blood gene modu...
(A) Modular gene expression (21) analysis of abatacept- versus placebo-treated subjects using GSEA (20). Horizontal lines indicate FDR = 0.10. Red dots indicate B cell modules (n = 4); dark red dots indicate CD19.mod; gray dots indicate other gene modules (n = 107). This analysis included 69, 58, and 56 abatacept-treated subjects at the 0, 84, and 728 day visits, respectively, and 31, 30, and 27 placebo-treated subjects. (B) GSEA analysis of abatacept-treated R versus NR subjects. There were 51, 43, and 44 NR and 18, 15, and 12 R subjects at each visit. (C) B cell gene expression for abatacept-treated R and NR subjects at each visit. B cell gene expression was calculated as median [log2(CD19.mod gene RPM +1)]. Two-sided Wilcoxon P values for group comparisons are indicated. P values are presented without multiple testing correction. **P < 1 × 10–2. (D) B cell gene expression for abatacept-treated subjects versus rate of C-peptide loss. P values were calculated using a linear model (B cell gene expression ~ rate of progression). Blue lines indicate slope calculated by linear model; gray shading indicates the standard error.