Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Blood. 2013 May 9;121(19):3936-45, S1. doi: 10.1182/blood-2012-09-457135. Epub 2013 Mar 26.
Current treatment of hemophilia consists of the administration of recombinant clotting factors, such as factor VIII (FVIII). However, patients with severe hemophilia can mount immune responses targeting therapeutically administered FVIII through inhibitory immunoglobulins that limit treatment efficacy. Induction of immune tolerance to FVIII in hemophilia has been extensively studied but remains an unmet need. We found that nondepleting anti-CD4 monoclonal antibodies (mAbs) are effective in inducing long-term tolerance to FVIII in different strains of hemophilic mice. Tolerance induction was facilitated when anti-CD4 mAbs were administered together with FVIII adsorbed in an adjuvant (alum). The observed state of tolerance was antigen specific, with mice remaining immune competent to respond to different antigens. Importantly, we found that following immunization with FVIII, the primed cells remained susceptible to tolerance induction. Studies with Foxp3-deficient and interleukin 10 (IL-10)-deficient mice demonstrated that the underlying tolerance mechanism is Foxp3 independent but requires IL-10. Our data show that an adjuvant, when administered together with a tolerizing agent such as nondepleting anti-CD4, can facilitate the induction of long-term tolerance to recombinant proteins, possibly not only in hemophilia but also in other diseases that are treated with potentially immunogenic therapeutics.
目前，血友病的治疗方法包括使用重组凝血因子，如因子 VIII（FVIII）。然而，严重血友病患者会通过抑制性免疫球蛋白产生针对治疗性给予的 FVIII 的免疫反应，从而限制治疗效果。在血友病中诱导对 FVIII 的免疫耐受已被广泛研究，但仍然是一个未满足的需求。我们发现，非耗竭性抗 CD4 单克隆抗体（mAb）在不同品系的血友病小鼠中诱导 FVIII 长期耐受是有效的。当抗 CD4 mAb 与在佐剂（明矾）中吸附的 FVIII 一起给予时，诱导耐受更容易。观察到的耐受状态是抗原特异性的，小鼠对不同抗原仍然具有免疫应答能力。重要的是，我们发现，在用 FVIII 免疫后，被激活的细胞仍然容易被诱导耐受。在 Foxp3 缺陷和白细胞介素 10（IL-10）缺陷小鼠中的研究表明，潜在的耐受机制不依赖于 Foxp3，但需要 IL-10。我们的数据表明，佐剂与非耗竭性抗 CD4 等耐受诱导剂一起使用时，可以促进对重组蛋白的长期耐受的诱导，可能不仅在血友病中，而且在其他用潜在免疫原性治疗药物治疗的疾病中也是如此。
