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 3

Covariation of age, treatment response, immune cell levels, and rate of progression.

Options: View larger image (or click on image) Download as PowerPoint
Covariation of age, treatment response, immune cell levels, and rate of ...
(A) Volcano plots of gene expression differences related to age of T1D onset (as a continuous variable) in abatacept-treated subjects (rate of progression ~ age at onset model). Plots are as in Figure 2B. Sample numbers were as in Figure 1A. (B) Slow progressors tend to be older at diagnosis. Shown are the rate of progression versus age at diagnosis for each subject. Comparisons between groups were determined using a linear model: rate of progression ~ age at diagnosis + group + age at diagnosis:group. This model contained fixed-effect terms for age at diagnosis and group; an interaction term for age at diagnosis and group (i.e., changes by group over age at diagnosis). P values for age, group, and age:group interaction terms are represented by asterisks. We obtained qualitatively similar results with more complex models. This analysis included 30 placebo-treated subjects and 43 and 14 fast and slow progressors, respectively. (C) Younger fast progressors express higher levels of B cell genes. Shown are the levels of B cell gene expression (median CD19.mod) at day 84 versus age at diagnosis. P values were determined using a linear model as in B. Sample numbers were as in Figure 3B. (D) Older slow progressors express higher levels of neutrophil genes. Shown are the levels of neutrophil gene expression (MPO.mod) at day 84 versus age at diagnosis. P values were determined using a linear model as in B. Sample numbers were as in B. *****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.