Title

Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy.

Document Type

Article

Publication Date

12-1-2017

Keywords

Animals, B-Cell Activating Factor, B-Cell Activation Factor Receptor, B-Lymphocytes, Regulatory, Cell Proliferation, Cells, Cultured, Combined Modality Therapy, Diabetes Mellitus, Type 1, Humans, Immunoglobulin Fc Fragments, Immunosuppression, Immunotherapy, Interleukin-10, Lymphocyte Depletion, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Rituximab, T-Lymphocytes

JAX Source

J Immunol 2017 Dec 1; 199(11):3757-3770

PMID

29055002

DOI

https://doi.org/10.4049/jimmunol.1700822

Grant

DK46266, DK95735, DK020351, DK111078, CA034196

Abstract

In NOD mice and also likely humans, B lymphocytes play an important role as APC-expanding autoreactive T cell responses ultimately causing type 1 diabetes (T1D). Currently, humans at high future T1D risk can only be identified at late prodromal stages of disease indicated by markers such as insulin autoantibodies. When commenced in already insulin autoantibody+ NOD mice, continuous BAFFR-Fc treatment alone or in combination with anti-CD20 (designated combo therapy) inhibited T1D development. Despite eliciting broader B lymphocyte depletion, continuous combo therapy afforded no greater T1D protection than did BAFFR-Fc alone. As previously observed, late disease stage-initiated anti-CD20 monotherapy did not inhibit T1D, and in this study was additionally found to be associated with development of drug-blocking Abs. Promisingly, NOD mice given transient late disease stage BAFFR-Fc monotherapy were rendered T1D resistant. However, combo treatment abrogated the protective effect of transient BAFFR-Fc monotherapy. NOD mice receiving transient BAFF blockade were characterized by an enrichment of regulatory B lymphocytes that inhibit T1D development through IL-10 production, but this population is sensitive to deletion by anti-CD20 treatment. B lymphocytes from transient BAFFR-Fc-treated mice suppressed T cell proliferation to a greater extent than did those from controls. Proportions of B lymphocytes expressing CD73, an ecto-enzyme operating in a pathway converting proinflammatory ATP to anti-inflammatory adenosine, were also temporarily increased by transient BAFFR-Fc treatment, but not anti-CD20 therapy. These collective studies indicate transient BAFFR-Fc-mediated B lymphocyte depletion elicits long-term T1D protection by enriching regulatory B lymphocytes that are deleted by anti-CD20 cotherapy. J Immunol 2017 Dec 1; 199(11):3757-3770.