Loss of Intra-Islet CD20 Expression May Complicate Efficacy of B-Cell–Directed Type 1 Diabetes Therapies

Abstract

OBJECTIVEConsistent with studies in NOD mice, early clinical trials addressing whether depletion of B cells by the Rituximab CD20-specific antibody provides an effective means for type 1 diabetes reversal have produced promising results. However, to improve therapeutic efficacy, additional B-cell–depleting agents, as well as attempts seeking diabetes prevention, are being considered.RESEARCH DESIGN AND METHODSAutoantibodies, including those against insulin (IAAs), are used to identify at-risk subjects for inclusion in diabetes prevention trials. Therefore, we tested the ability of anti-CD20 to prevent diabetes in NOD mice when administered either before or after IAA onset.RESULTSThe murine CD20-specific 18B12 antibody that like Rituximab, depletes the follicular (FO) but not marginal zone subset of B cells, efficiently inhibited diabetes development in NOD mice in a likely regulatory T-cell–dependent manner only when treatment was initiated before IAA detection. One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events. However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.CONCLUSIONSThese findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.

NOD.H-2h4 Mice

“…These results are consistent with our studies using anti-CD20 to deplete B cells in WT NOD.H2h4 mice, since anti-CD20 inhibits development of SAT, but SAT anti-CD20-treated mice develop SAT comparable to isotype-treated controls when Treg are transiently depleted . Other groups have also shown that depletion of Treg abrogates the ability of anti-CD20 to suppress diabetes (Serreze et al, 2011) and arthritis (Hamel et al, 2011). Our studies demonstrating an important role for Treg as the basis for the resistance of B cell-deficient mice to other spontaneous autoimmune diseases was demonstrated in our studies with B À/À NOD mice where transient Treg depletion resulted in development of thyroiditis, diabetes, and SS.…”

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

“…Finally, the murine CD20-specific 18B12 antibody that, like rituximab, depletes the follicular (FO) but not marginal zone subset of B cells (MZB), efficiently inhibited diabetes development in NOD mice in a likely regulatory T-celldependent manner only when treatment was initiated before IAA detection. The latter observations suggest that MZBs, which are known to be potent APCs, may well play a role in the chain of events leading to overt diabetes (Serreze et al 2011).…”

CD19+CD24hiCD38hi regulatory B cells are associated with insulin resistance in type I Hashimoto's thyroiditis in Chinese females

“…However, minimal work has been conducted to investigate the association between Bregs in the immune response and the occurrence of HT. Immune-mediated injury serves an important role in the pathogenesis of insulin resistance and diabetes mellitus (DM) (13,14). A previous study indicated that patients with HT had significantly increased peripheral blood CD19 + CD24 + CD27 + Bregs, and the increased percentage of CD19 + CD24 + CD27 + Bregs was correlated with fasting insulin secretion and fasting insulin resistance in patients with HT (8 In order to eliminate the effect of thyroid hormones on insulin signaling and glucose regulation in the present study, only patients with type I HT who had normal thyroid function and were not on hormone treatment were included.…”