Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy
Year: 2017
Type: article
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.
Source: The Journal of Immunology
Institutions: Tufts University, Jackson Laboratory, University of Florida
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: The Jackson Laboratory Center for Precision Genetics: From New Models to Novel Therapeutics, DIABETOGENIC ROLE OF H-2G7 CLASS I ALLELES IN NOD MICE, Diabetogenic Role of MHC Class I Alleles in NOD Mice, Optimizing B-lymphocyte Therapeutic Targeting Strategies in Autoimmune Diabetes, Advancing HLA-"Humanized" Models for T1D Therapy Development, Immune Function and the Progression to Type 1 Diabetes, B-lymphocyte Targeting Therapies for Autoimmune Diabetes, Cancer Center Support (CORE) Grant
OpenAlex ID: W2765610946