Elevated T cell levels in peripheral blood predict poor clinical response following rituximab treatment in new-onset type 1 diabetes

Abstract

Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab. RNA sequencing (RNA-seq) analysis of whole-blood samples from this trial revealed a transient increase in heterogeneous T cell populations, which were associated with decreased pharmacodynamic activity of rituximab, increased proliferative responses to islet antigens, and more rapid C-peptide loss. Our findings illustrate complexity in hematopoietic remodeling that accompanies B cell depletion by rituximab, which impacts and predicts therapeutic efficacy in T1D. Our data also suggest that a combination of rituximab with therapy targeting CD4 + T cells may be beneficial for T1D subjects.

Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes

“…We validated these findings with CBC and flow cytometry data and showed that they can be used to predict differential benefits of immunomodulatory therapy. In combination with other recent work on response to immunotherapy (9)(10)(11)(39)(40)(41), these results point toward precision targeting and modulation of therapy to achieve optimal benefits.…”

“…In order to interrogate immunological differences with rate of T1D progression in an unbiased manner, we used whole blood gene expression profiling by RNA-seq (see Methods). We have previously used this approach to investigate response to treatment in new-onset T1D, including variation in rates of C-peptide loss following immunotherapy (9)(10)(11). We performed RNA-seq analysis on all subjects for whom sufficient samples were available; included subjects did not differ from total study populations in age at T1D diagnosis, sex, baseline C-peptide, baseline HbA1c, or rate of C-peptide change ( Table 1).…”

“…We then used additional data to evaluate the relationship between B cells and response to treatment. RNAseq data were available for a subset of the trial participants, as described previously (9); this subset did not differ significantly from the original trial population in age, sex, or C-peptide characteristics. In the subset of participants with RNA-seq data, placebo-arm subjects with high B cell gene expression showed a more rapid loss of C-peptide ( Figure 5A; P = 0.004 for slope).…”

“…Second, we aimed to characterize the immunological heterogeneity of T1D, with the goal of identifying additional therapeutic targets and/or personalizing treatment. We have previously used whole blood RNA-seq to detect correlates of C-peptide loss in clinical trials of new-onset T1D (9,10), as applied by Linsley et al to abatacept treatment in an accompanying article (11). This method allows unbiased examination of a large number of immune processes with a single assay.…”

In-vivo assessment of T cell kinetics in individuals at risk for type 1 diabetes

“…However, as in all immune therapy, there is a range of responses among those treated with active drug. Poor responders to the B cell depletion therapy rituximab were found to have an increase in activated T cell gene transcripts , and those who had poor responses to abatacept had an increase in B cell gene transcripts . Whether or not these transcriptional changes were due to changes in proliferation could be addressed in subsequent clinical trials, with therapies expected to impact T cell turnover using the short heavy glucose labeling protocol described here.…”