Instituto de Biomedicina y Biotecnología de Cantabria, CSIC-Universidad de Cantabria-SODERCAN, Santander, Spain.
IDIVAL and Universidad de Cantabria, Santander, Spain.
Arthritis Rheumatol. 2020 Sep;72(9):1547-1558. doi: 10.1002/art.41272. Epub 2020 Jul 30.
The transforming growth factor β (TGFβ) inhibitor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGFβ and interleukin-2 (IL-2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti-BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease.
Development of Saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n = 18-30 mice per group), imiquimod-induced skin psoriasis (n = 20-30 mice per group), or type II collagen-induced arthritis (CIA) (n = 13-16 mice per group) was analyzed in a total of 2-5 different experiments with either wild-type (WT) or BAMBI-deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti-BAMBI), a mouse IgG1 anti-TNP isotype control, anti-CD25, or anti-TGFβ mAb.
Treatment of normal mice with IgG1 anti-BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL-17-producing cells, and was dependent on the level of TGFβ activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti-BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls).
These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.
转化生长因子β（TGFβ）抑制剂 BAMBI（骨形态发生蛋白和激活素膜结合抑制剂）已被证明可通过调节 TGFβ 和白细胞介素 2（IL-2）信号强度来控制 CD4+T 淋巴细胞分化为耐受 Treg 细胞或致病性 Th17 细胞。本研究旨在通过使用新型抗 BAMBI 单克隆抗体（mAb）在不同的慢性皮肤和关节炎症/自身免疫性疾病的实验性小鼠模型中探索这种药理抑制策略的潜在有益效果。
共进行了 2-5 项不同的实验，分析了酿酒酵母甘露聚糖诱导的银屑病关节炎（MIP）（每组 18-30 只小鼠）、咪喹莫特诱导的皮肤银屑病（每组 20-30 只小鼠）或 II 型胶原诱导的关节炎（CIA）（每组 13-16 只小鼠）的发病情况。使用未经处理或用 mAb B101.37（鼠 IgG1 抗 BAMBI）、鼠 IgG1 抗 TNP 同种型对照、抗 CD25 或抗 TGFβ mAb 处理的野生型（WT）或 BAMBI 缺陷 B10.RIII 小鼠。
用 IgG1 抗 BAMBI mAb 克隆 B101.37 治疗正常小鼠可导致体内 Treg 细胞扩增，并在 MIP 小鼠中具有预防和治疗作用（与对照组相比，每种情况均 P<0.05）。发现对疾病进展的保护作用是由 Treg 细胞介导的，Treg 细胞控制致病性 IL-17 产生细胞的激活和扩增，并依赖于 TGFβ 活性水平。此外，用 B101.37 mAb 治疗可阻断咪喹莫特诱导的皮肤银屑病的发展和 CIA 在小鼠中的发展（与对照组相比，每种情况均 P<0.05）。最后，用 IgM 抗 BAMBI mAb B143.14 抑制 BAMBI 的药理作用也增强了 Treg 细胞在体外的抑制活性（与对照组相比，P<0.001）。
这些在小鼠模型中的结果将 BAMBI 确定为慢性炎症性疾病和其他由 Treg 细胞调节的病理状况的有希望的新治疗靶标。
