Title

Loss of intra-islet CD20 expression may complicate efficacy of B-cell-directed type 1 diabetes therapies.

Document Type

Article

Publication Date

2011

Keywords

Antibodies-Monoclonal-Murine-Derived, Antigens-CD20, Autoantibodies, B-Lymphocytes, Diabetes-Mellitus-Type-1, Disease-Progression, Female, Hypoglycemic-Agents, Islets-of-Langerhans, Lymphocyte-Depletion, Mice-Inbred-NOD, Mice-SCID, Molecular-Targeted-Therapy, Plasma-Cells, Prediabetic-State

JAX Location

see Reprint collection (a pdf is available)

JAX Source

Diabetes 2011 Nov; 60(11):2914-21.

Abstract

OBJECTIVE: Consistent 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 METHODS: Autoantibodies, 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. RESULTS: The 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. CONCLUSIONS: These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.

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