Frontiers in Immunology ( IF 7.3 ) Pub Date : 2020-02-19 , DOI: 10.3389/fimmu.2020.00393 Sandrine Delignat 1 , Julie Rayes 1 , Suryasarathi Dasgupta 1 , Bagirath Gangadharan 1 , Cécile V Denis 2 , Olivier D Christophe 2 , Jagadeesh Bayry 1 , Srinivas V Kaveri 1 , Sébastien Lacroix-Desmazes 1
The development of an immune response against therapeutic factor VIII is the major complication in hemophilia A patients. Oligomannose carbohydrates at N239 and/or N2118 on factor VIII allow its binding to the macrophage mannose receptor expressed on human dendritic cells, thereby leading to factor VIII endocytosis and presentation to CD4+ T lymphocytes. Here, we investigated whether altering the interaction of factor VIII with mannose-sensitive receptors on antigen-presenting cells may be a strategy to reduce factor VIII immunogenicity. Gene transfer experiments in factor VIII-deficient mice indicated that N239Q and/or N2118Q factor VIII mutants have similar specific activities as compared to non-mutated factor VIII; N239Q/N2118Q mutant corrected blood loss upon tail clip. Production of the corresponding recombinant FVIII mutants or light chains indicated that removal of the N-linked glycosylation site at N2118 is sufficient to abrogate
中文翻译:
去除人单核细胞衍生的树突状细胞在Asn2118上终止甘露糖的聚糖使FVIII呈递。
抗治疗因子VIII的免疫反应的发展是A型血友病患者的主要并发症。因子VIII的N239和/或N2118处的寡甘露糖碳水化合物使其与人树突状细胞上表达的巨噬细胞甘露糖受体结合,从而导致因子VIII内吞并呈递给CD4 + T淋巴细胞。在这里,我们研究了改变因子VIII与抗原呈递细胞上甘露糖敏感受体的相互作用是否可能是降低因子VIII免疫原性的策略。在缺乏因子VIII的小鼠中进行的基因转移实验表明,与非突变因子VIII相比,N239Q和/或N2118Q因子VIII突变体具有相似的比活性;N239Q / N2118Q突变体纠正了尾夹后的失血。