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

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 11; pp. 2914 - 2921
• Main Authors: Serreze, David V., Chapman, Harold D., Niens, Marijke, Dunn, Robert, Kehry, Marilyn R., Driver, John P., Haller, Michael, Wasserfall, Clive, Atkinson, Mark A.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.11.2011
• Subjects: Animals; Antibodies; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antigens, CD20 - chemistry; Antigens, CD20 - metabolism; Autoantibodies - analysis; Autoimmunity; B cells; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Care and treatment; Clinical trials; Development and progression; Diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - prevention & control; Disease prevention; Disease Progression; Female; Flow cytometry; Hyperglycemia; Hypoglycemic Agents - therapeutic use; Immunology; Immunology and Transplantation; Islets of Langerhans - drug effects; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Leukocytes; Lymphocyte Depletion; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Pathogenesis; Physiological aspects; Plasma Cells - drug effects; Plasma Cells - immunology; Plasma Cells - metabolism; Prediabetic State - blood; Prediabetic State - immunology; Prediabetic State - metabolism; Research design; Rituximab; Type 1 diabetes; United States
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db11-0705

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. 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. 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. These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.