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

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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC5698153 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Wang Qiming Q Racine Jeremy J JJ Ratiu Jeremy J JJ Wang Shu S Ettinger Rachel R Wasserfall Clive C Atkinson Mark A MA Serreze David V DV

Journal of immunology (Baltimore, Md. : 1950) 20171020 11

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<sup>+</sup> NOD mice, continuous BAFFR-Fc treatment alone or in combination with anti-CD20 (designated combo therapy) inhibited T1D devel ...[more]

PMID: 29055002

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Project description:Memory B-cell dysfunctions and inefficient antibody response suggest germinal center (GC) impairments during HIV/SIV infection with possible contribution of overproduced B-cell activating factor (BAFF). To address this question, we compared proportions and functions of various B-cell subsets and follicular helper T-cells (TFH) in untreated (Placebo) and BR3-Fc treated (Treated) SIV-infected macaques. From day 2 post-infection (dpi), Treated macaques received one weekly injection of BR3-Fc molecule, a soluble BAFF antagonist, for 4 weeks. Whereas, the kinetics of CD4+ T-cell loss and plasma viral loads were comparable in both groups, BAFF blockade delayed the peak of inflammatory cytokines (CXCL10, IFNα), impaired the renewal of plasmacytoid dendritic cells and fostered the decline of plasma CXCL13 titers after 14 dpi. In Treated macaques, proportions of total and naïve B-cells were reduced in blood and spleen whereas SIV-induced loss of marginal zone (MZ) B-cells was only accentuated in blood and terminal ileum. Proportions of spleen GC B-cells and TFH were similar in both groups, with CD8+ T-cells and rare Foxp3+ being present in spleen GC. Regardless of treatment, sorted TFH produced similar levels of IL21, CXCL13, and IFNγ but no IL2, IL4, or BAFF and exhibited similar capacities to support IgG production by autologous or heterologous B-cells. Consistently, most TFH were negative for BAFF-R and TACI. Higher proportions of resting and atypical (CD21lo) memory B-cells were present in Treated macaques compared to Placebo. In both groups, we found higher levels of BAFF-R expression on MZ and resting memory B-cells but low levels on atypical memory B-cells. TACI was present on 20-30% of MZ, resting and atypical memory B-cells in Placebo macaques. BAFF blockade decreased TACI expression on these B-cell subsets as well as titers of SIV-specific and vaccine-specific antibodies arguing for BAFF being mandatory for plasma cell survival. Irrespective of treatment, GC B-cells expressed BAFF-R at low level and were negative for TACI. In addition to key information on spleen BAFF-R and TACI expression, our data argue for BAFF contributing to the GC reaction in terminal ileum but being dispensable for the generation of atypical memory B-cells and GC reaction in spleen during T-dependent response against SIV.

Dataset Information

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

Publications

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

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