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CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice

机译:CD4 + FOXP3 +调节性T细胞可在质粒介导的基因疗法治疗的血友病小鼠中长期调节因子VIII特异性免疫反应

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摘要

Gene transfer of a factor VIII (FVIII) plasmid into hemophilia A (HemA) mice achieved supraphysiologic FVIII expression, but triggered production of high-titer FVIII-specific antibodies and loss of functional FVIII activity. To test whether FVIII-specific regulatory T cells (Tregs) can modulate immune responses against FVIII, we developed a HemA mouse model in which all T cells overexpressed Foxp3 (HemA/Foxp3-Tg). FVIII plasmid therapy did not induce antibody production in HemA/Foxp3-Tg mice. CD4+Foxp3+ T cells isolated from plasmid-treated HemA/Foxp3-Tg mice significantly suppressed proliferation of FVIII-stimulated CD4+ effector T cells. The percentage of CD4+ T cells expressing CD25, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4 increased significantly in spleen and peripheral blood for 9 weeks. Mice receiving adoptively transferred Tregs from FVIII-exposed HemA/Foxp3-Tg mice produced significantly reduced antibody titers compared with controls after initial challenge with FVIII plasmid and second challenge 16 weeks after first plasmid treatment. Adoptively transferred Tregs engrafted and distributed at 2% to 4% in the Treg compartment of blood, lymph nodes, and spleens of the recipient mice and induced activation of endogenous Tregs; the engraftment decreased to negligible levels over 8 to 12 weeks. Antigen-specific Tregs can provide long-lasting protection against immune responses in vivo and limit recall responses induced by a second challenge via infectious tolerance.
机译:凝血因子VIII(FVIII)质粒向血友病A(HemA)小鼠的基因转移实现了超生理学FVIII表达,但触发了高滴度FVIII特异性抗体的产生和功能性FVIII活性的丧失。为了测试FVIII特异性调节性T细胞(Tregs)是否可以调节针对FVIII的免疫反应,我们开发了一个HemA小鼠模型,其中所有T细胞都过表达Foxp3(HemA / Foxp3-Tg)。 FVIII质粒疗法未在HemA / Foxp3-Tg小鼠中诱导抗体产生。从质粒处理的HemA / Foxp3-Tg小鼠分离的CD4 + Foxp3 + T细胞可显着抑制FVIII刺激的CD4 +效应T细胞的增殖。在脾脏和外周血中,表达CD25,糖皮质激素诱导的肿瘤坏死因子受体和细胞毒性T淋巴细胞抗原4的CD4 + T细胞百分比持续9周显着增加。与暴露于FVIII质粒的HemA / Foxp3-Tg小鼠的过继转移的Treg相比,小鼠接受FVIII质粒初始攻击后和第一次质粒处理16周后的第二次攻击相比,产生的抗体效价显着降低。过继转移的Tregs移植并以2%至4%的比例分布在受体小鼠的血液,淋巴结和脾脏的Treg隔室中,并诱导内源性Tregs的活化。在8至12周内,移入量降低到可以忽略的水平。抗原特异性Treg可提供针对体内免疫反应的持久保护,并通过传染性耐受性限制第二次攻击诱导的召回反应。

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