IgD-Fc-Ig fusion protein, a new biological agent, is constructed by linking a segment of human IgD-Fc with a segment of human IgG1-Fc, which specifically blocks the IgD-IgDR pathway and selectively inhibits the abnormal proliferation, activation, and differentiation of T cells. In this study we investigated whether IgD-Fc-Ig exerted therapeutic effects in collagen-induced arthritis (CIA) rats. CIA rats were treated with IgD-Fc-Ig (1, 3, and 9 mg/kg) or injected with biological agents etanercept (3 mg/kg) once every 3 days for 40 days. In the PBMCs and spleen lymphocytes of CIA rats, both T and B cells exhibited abnormal proliferation; the percentages of CD3⁺ total T cells, CD3⁺CD4⁺ Th cells, CD3⁺CD4⁺CD25⁺-activated Th cells, Th1(CD4⁺IFN-γ⁺), and Th17(CD4⁺IL-17⁺) were significantly increased, whereas the Treg (CD4⁺CD25⁺Foxp3⁺) cell percentage was decreased. IgD-Fc-Ig administration dose-dependently decreased the indicators of arthritis; alleviated the histopathology of spleen and joint; reduced serum inflammatory cytokines levels; decreased the percentages of CD3⁺ total T cells, CD3⁺CD4⁺ Th cells, CD3⁺CD4⁺CD25⁺-activated Th cells, Th1 (CD4⁺IFN-γ⁺), and Th17(CD4⁺IL-17⁺); increased Treg (CD4⁺CD25⁺Foxp3⁺) cell percentage; and down-regulated the expression of key molecules in IgD-IgDR-Lck-NF-κB signaling (p-Lck, p-ZAP70, p-P38, p-NF-κB65). Treatment of normal T cells with IgD (9 μg/mL) in vitro promoted their proliferation. Co-treatment with IgD-Fc-Ig (0.1–10 μg/mL) dose-dependently decreased IgD-stimulated T cell subsets percentages and down-regulated the IgD-IgDR-Lck-NF-κB signaling. In summary, this study demonstrates that IgD-Fc-Ig alleviates CIA and regulates the functions of T cells through inhibiting IgD-IgDR-Lck-NF-κB signaling.

IgD-Fc-Ig融合蛋白是一种新型生物制剂，通过连接一段人IgD-Fc与一段人IgG1-Fc构建，特异性阻断IgD-IgDR通路，选择性抑制异常增殖、活化、和 T 细胞的分化。在这项研究中，我们调查了 IgD-Fc-Ig 是否在胶原诱导的关节炎 (CIA) 大鼠中发挥治疗作用。CIA 大鼠每 3 天用 IgD-Fc-Ig（1、3 和 9 mg/kg）治疗或注射生物制剂依那西普（3 mg/kg）一次，持续 40 天。CIA大鼠的外周血单个核细胞和脾淋巴细胞中，T细胞和B细胞均出现异常增殖；CD3 ⁺总 T 细胞、CD3 ⁺ CD4 ⁺ Th 细胞、CD3 ⁺ CD4 ⁺ CD25的百分比⁺激活的 Th 细胞、Th1(CD4 ⁺ IFN-γ ⁺ ) 和 Th17(CD4 ⁺ IL-17 ⁺ ) 显着增加，而 Treg (CD4 ⁺ CD25 ⁺ Foxp3 ⁺ ) 细胞百分比降低。IgD-Fc-Ig给药剂量依赖性降低关节炎指标；减轻脾脏和关节的组织病理学；降低血清炎性细胞因子水平；降低 CD3 ⁺总 T 细胞、CD3 ⁺ CD4 ⁺ Th 细胞、CD3 ⁺ CD4 ⁺ CD25 ⁺激活的 Th 细胞、Th1 (CD4 ⁺ IFN-γ ⁺) 和 Th17(CD4 ⁺ IL-17 ⁺ ); 增加 Treg (CD4 ⁺ CD25 ⁺ Foxp3 ⁺ ) 细胞百分比；并下调 IgD-IgDR-Lck-NF-κB 信号转导中关键分子的表达（p-Lck、p-ZAP70、p-P38、p-NF-κB65）。在体外用 IgD (9 μg/mL) 处理正常 T 细胞促进了它们的增殖。与 IgD-Fc-Ig (0.1–10 μg/mL) 共同处理剂量依赖性地降低 IgD 刺激的 T 细胞亚群百分比并下调 IgD-IgDR-Lck-NF-κB 信号传导。总之，本研究表明，IgD-Fc-Ig 通过抑制 IgD-IgDR-Lck-NF-κB 信号传导来缓解 CIA 并调节 T 细胞的功能。