Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Amherst, NY 14260, USA.
Clin Immunol. 2011 Feb;138(2):135-45. doi: 10.1016/j.clim.2010.10.006. Epub 2010 Nov 20.
A major clinical complication in the treatment of Hemophilia A using exogenously administered recombinant Factor VIII (FVIII) is the development of neutralizing antibodies. It has been shown previously that FVIII complexed with phosphatidylserine (PS) reduces the development of total and neutralizing antibody titers in hemophilic mice. The effect of complexation of FVIII with PS upon dendritic cell (DC) uptake, maturation and processing, T-cell proliferation and cytokine secretion profiles was investigated. Flow cytometric studies of DC showed that PS inhibited the up-regulation of cell surface co-stimulatory markers (CD86 and CD40). PS reduced T-cell proliferation and significantly increased levels of TGF-β and IL-10 but reduced secretion of IL-6 and IL-17 compared to controls. The data suggest that PS reduces immunogenicity of FVIII by regulating dendritic cell maturation and subsequent T-lymphocyte activity through modulation of cytokine secretion. A possible mechanism for PS-mediated induction of FVIII tolerance is discussed.
在使用外源性重组因子 VIII（FVIII）治疗 A 型血友病时，一个主要的临床并发症是产生中和抗体。先前已经表明，与磷脂酰丝氨酸（PS）结合的 FVIII 可降低血友病小鼠中总抗体和中和抗体滴度的产生。研究了 FVIII 与 PS 复合对树突状细胞（DC）摄取、成熟和处理、T 细胞增殖和细胞因子分泌谱的影响。对 DC 的流式细胞术研究表明，PS 抑制细胞表面共刺激标记物（CD86 和 CD40）的上调。与对照组相比，PS 降低了 T 细胞增殖，并显著增加了 TGF-β和 IL-10 的水平，但减少了 IL-6 和 IL-17 的分泌。数据表明，PS 通过调节树突状细胞成熟和随后的 T 淋巴细胞活性，通过调节细胞因子分泌，降低了 FVIII 的免疫原性。讨论了 PS 介导的 FVIII 耐受诱导的可能机制。
