{"title":"以非肥胖糖尿病小鼠为自发模型,抑制 BAFF 和 B 细胞消耗对 Sjögren 病的疗效。","authors":"Renaud Felten, Anne-Perrine Foray, Pascal Schneider, Cindy Marquet, Coralie Pecquet, Fanny Monneaux, Hélène Dumortier, Jean Sibilia, Fabrice Valette, Lucienne Chatenoud, Jacques-Eric Gottenberg","doi":"10.1136/rmdopen-2024-004112","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD.</p><p><strong>Material and methods: </strong>Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis.</p><p><strong>Results: </strong>BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3<sup>+</sup> regulatory and CD3<sup>+</sup>CD4<sup>-</sup>CD8<sup>-</sup> double negative T-cell numbers in SGs.</p><p><strong>Conclusion: </strong>A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment.</p>","PeriodicalId":21396,"journal":{"name":"RMD Open","volume":null,"pages":null},"PeriodicalIF":5.1000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367362/pdf/","citationCount":"0","resultStr":"{\"title\":\"Efficacy of BAFF inhibition and B-cell depletion in non-obese diabetic mice as a spontaneous model for Sjögren's disease.\",\"authors\":\"Renaud Felten, Anne-Perrine Foray, Pascal Schneider, Cindy Marquet, Coralie Pecquet, Fanny Monneaux, Hélène Dumortier, Jean Sibilia, Fabrice Valette, Lucienne Chatenoud, Jacques-Eric Gottenberg\",\"doi\":\"10.1136/rmdopen-2024-004112\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD.</p><p><strong>Material and methods: </strong>Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis.</p><p><strong>Results: </strong>BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3<sup>+</sup> regulatory and CD3<sup>+</sup>CD4<sup>-</sup>CD8<sup>-</sup> double negative T-cell numbers in SGs.</p><p><strong>Conclusion: </strong>A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. 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引用次数: 0
摘要
导言:从两项二期临床试验的结果可以推测,以B细胞活化因子(BAFF)为靶点对斯约戈伦病(SjD)具有治疗意义,但尚未在该病的动物模型中进行评估。我们的目的是评估该策略对 SjD NOD 小鼠模型中干燥和唾液腺(SG)浸润的疗效:用BAFF阻断单克隆抗体Sandy-2或同型对照组治疗10至18周龄的雌性NOD小鼠。通过刺激唾液流量来测量干燥度。唾液淋巴细胞浸润通过免疫组化进行评估。流式细胞术分析血液、SG、脾脏和淋巴结淋巴细胞亚群。通过转录组分析 SG mRNA 的表达:结果:抑制 BAFF 能明显减少 SG 淋巴细胞浸润,这与唾液流量成反比。治疗明显减少了 SG、血液、淋巴结和脾脏中的 B 细胞数量,增加了 SG 中 Foxp3+ 调节性和 CD3+CD4-CD8- 双阴性 T 细胞数量:结论:阻断 BAFF 和消耗 B 细胞的单克隆抗体对 SjD 的 NOD 小鼠模型有疗效。调节性T淋巴细胞数量的增加可能是该疗法有效的原因。
Efficacy of BAFF inhibition and B-cell depletion in non-obese diabetic mice as a spontaneous model for Sjögren's disease.
Introduction: The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD.
Material and methods: Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis.
Results: BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3+ regulatory and CD3+CD4-CD8- double negative T-cell numbers in SGs.
Conclusion: A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment.
期刊介绍:
RMD Open publishes high quality peer-reviewed original research covering the full spectrum of musculoskeletal disorders, rheumatism and connective tissue diseases, including osteoporosis, spine and rehabilitation. Clinical and epidemiological research, basic and translational medicine, interesting clinical cases, and smaller studies that add to the literature are all considered.