Mapping the T helper cell response to acid α-glucosidase in Pompe mice.
Mapping the T helper cell response to acid α-glucosidase in Pompe mice.
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DOI：
10.1016/j.ymgme.2012.03.009
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发表时间：
2012-06
影响因子：
3.8
通讯作者：
Herzog, Roland W.
中科院分区：
文献类型：
--
作者：
Nayak, Sushrusha;Sivakumar, Ramya;Cao, Ou;Daniell, Henry;Byrne, Barry J.;Herzog, Roland W.
庞贝氏症是一种神经肌肉疾病，由溶酶体酶酸性α-葡萄糖苷酶（GAA）的遗传性缺乏引起。由此产生的糖原积累会导致肌肉无力，严重的疾病会导致生命第一年因心肺衰竭而死亡。唯一可用的治疗，酶替代疗法（ERT）与重组GAA（rhGAA），是严重阻碍抗体反应，降低疗效和引起免疫毒性。目前，Pompe小鼠代表了用于开发新治疗和免疫学研究的唯一临床前模型。虽然已经描述了该模型中ERT后的抗体形成，但尚未研究潜在的T细胞应答。为了确定庞贝氏症小鼠对rhGAA的辅助性T细胞应答，使用ELISpot在GAA−/− 129 SVE小鼠中定位免疫显性CD 4 + T细胞表位。此外，测定了ERT期间针对rhGAA的细胞因子应答和抗体形成。在鉴定的三种CD 4 + T细胞表位中，只有表位IFLGPEPKSVVQ，预测为最强的MHC II结合剂，始终有助于IL-4的产生。产生IL-4的T细胞的频率显著高于产生IL-17或IFN-γ的细胞的频率，表明主要是Th 2细胞介导的应答。这一点得到了以下结果的进一步支持：IgG 1是ERT期间针对rhGAA的普遍抗体亚类，并且与该模型中IgE形成和速发型过敏反应的既往报告一致。这些结果将有助于在开发新疗法和耐受性方案期间在庞贝氏症小鼠中对rhGAA的免疫应答的机制研究。
Pompe disease is a neuromuscular disease caused by an inherited deficiency of the lysosomal enzyme acid α-glucosidase (GAA). The resulting accumulation of glycogen causes muscle weakness with the severe form of the disease resulting in death by cardiorespiratory failure in the first year of life. The only available treatment, enzyme replacement therapy (ERT) with recombinant GAA (rhGAA), is severely hampered by antibody responses that reduce efficacy and cause immunotoxicities. Currently, Pompe mice represent the only pre-clinical model for development of new treatments and for immunological studies. While antibody formation following ERT in this model has been described, the underlying T cell response has not been studied. In order to define the T helper response to rhGAA in Pompe mice, immunodominant CD4+ T cell epitopes were mapped in GAA−/− 129SVE mice using ELISpot. Additionally, cytokine responses and antibody formation against rhGAA during ERT were measured. Among the three CD4+ T cell epitopes identified, only epitope IFLGPEPKSVVQ, predicted to be the strongest MHC II binder, consistently contributed to IL-4 production. Frequencies of IL-4 producing T cells were considerably higher than those of IL-17 or IFN-γ producing cells, suggesting a predominantly Th2 cell mediated response. This is further supported by IgG1 being the prevalent antibody subclass against rhGAA during ERT and consistent with prior reports on IgE formation and anaphylaxis in this model. These results will facilitate mechanistic studies of the immune response to rhGAA in Pompe mice during development of new therapies and tolerance protocols.
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DOI：
10.1097/01.gim.0000218152.87434.f3
发表时间：
2006-05
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Kishnani PS;Steiner RD;Bali D;Berger K;Byrne BJ;Case LE;Crowley JF;Downs S;Howell RR;Kravitz RM;Mackey J;Marsden D;Martins AM;Millington DS;Nicolino M;O'Grady G;Patterson MC;Rapoport DM;Slonim A;Spencer CT;Tifft CJ;Watson MS
通讯作者：
Watson MS
影响因子：
20.3
作者：
Cao, Ou;Armstrong, Elina;Herzog, Roland W.
通讯作者：
Herzog, Roland W.
影响因子：
4.3
作者：
Nielsen M;Lundegaard C;Blicher T;Peters B;Sette A;Justesen S;Buus S;Lund O
通讯作者：
Lund O
影响因子：
12.4
作者：
Sun, Baodong;Kulis, Michael D.;Koeberl, Dwight D.
通讯作者：
Koeberl, Dwight D.
影响因子：
5.2
作者：
Nayak S;Sarkar D;Perrin GQ;Moghimi B;Hoffman BE;Zhou S;Byrne BJ;Herzog RW
通讯作者：
Herzog RW