The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells

Saulep-Easton, Damien; Vincent, Fabien B.; Quah, Pin Shie; Wei, Andrew H.; Ting, Stephen B.; Croce, Carlo M.; Tam, Constantine S.; Mackay, Fabienne

doi:10.1038/leu.2015.174

Cited by 78 publications

(73 citation statements)

References 57 publications

(85 reference statements)

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“…Moreover, we found an increase of CD73 in B10 cells in BAFFtg mice especially when they were tolerised with MTX. Interestingly, it has been previously shown that BAFF stimulation of B cells increased IL-10 production in the supernatant22 and that B cells from BAFFtg mice could secrete more IL-10 23. Since B10 cells require in vitro activation to be studied, we sought to also explore Breg precursors as described previously 19…”

Section: Discussionmentioning

confidence: 99%

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Bitoun

Nocturne

et al. 2018

Ann Rheum Dis

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ObjectivesTNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation.MethodsWe treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs).We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation.ResultsIn BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy.ConclusionMTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.

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Section: Discussionmentioning

confidence: 99%

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Bitoun

Nocturne

et al. 2018

Ann Rheum Dis

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“…Upon CSF-1R neutralization, NLC were virtually undetectable in these cultures (Figure 1C, D, E). In contrast, neutralization of the cytokines IL-10 and IL-6, which have been previously implicated in CLL and/or NLC biology (15, 27–30), did not significantly inhibit NLC generation. CSF-1 was at or below the limit of detection (by ELISA) in culture supernatants obtained from NLC cultures (data not shown).…”

Section: Resultsmentioning

confidence: 61%

Colony-Stimulating Factor-1 Receptor Is Required for Nurse-like Cell Survival in Chronic Lymphocytic Leukemia

Polk

Wang

et al. 2016

Clinical Cancer Research

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Purpose Monocytes and their progeny are abundant constituents of the tumor microenvironment in lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). Monocyte-derived cells, including nurse-like cells (NLC) in CLL, promote lymphocyte proliferation and survival, confer resistance to chemotherapy, and are associated with more rapid disease progression. Colony-stimulating factor-1 receptor (CSF-1R) regulates the homeostatic survival of tissue-resident macrophages. Therefore, we sought to determine whether CSF-1R is similarly required for NLC survival. Experimental Design CSF-1R expression by NLC was examined by flow cytometry and immunohistochemistry. CSF-1R blocking studies were performed using an antagonistic monoclonal antibody to examine its role in NLC generation and in CLL survival. A rational search strategy was performed to identify a novel tyrosine kinase inhibitor (TKI) targeting CSF-1R. The influence of TKI-mediated CSF-1R inhibition on NLC and CLL viability was examined. Results We demonstrated that the generation and survival of NLC in CLL is dependent upon CSF-1R signaling. CSF-1R blockade is associated with significant depletion of NLC and consequently inhibits CLL B-cell survival. We found that the JAK2/FLT3 inhibitor pacritinib suppresses CSF-1R signaling, thereby preventing the generation and survival of NLC and impairs CLL B-cell viability. Conclusions CSF-1R is a novel therapeutic target that may be exploited in lymphoproliferative disorders, like CLL, that are dependent upon lymphoma-associated macrophages.

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“…40,43 Consistently, hypoxia protected CLL cells from drug-induced apoptosis and triggered production of IL-10, which is considered the hallmark cytokine for regulatory B cells. 57 Monocytes in hypoxic conditions differentiated more readily into M2 macrophages, becoming more efficient supporters of CLL survival, while T lymphocytes showed impaired proliferation and increased expression of Treg markers. The effects converged to create ideal conditions for tumor growth in closed environments.…”

Section: Discussionmentioning

confidence: 99%

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

et al. 2016

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Key Points• Hypoxia shapes the CLL lymph node microenvironment by acting through the A2A adenosine receptor.• Inhibiting the A2A adenosine receptor counteracts the effects of hypoxia on CLL cells, macrophages, and T lymphocytes. adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients.

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The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells

Cited by 78 publications

References 57 publications

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Colony-Stimulating Factor-1 Receptor Is Required for Nurse-like Cell Survival in Chronic Lymphocytic Leukemia

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment

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