Immune Tolerance to Factor IX in Hemophilia B

描述（由申请人提供）：血友病B是一种遗传性疾病， 凝血因子IX缺乏导致的血友病B的当前治疗 患者是蛋白质治疗和临床试验目前正在进行中的一个 基因治疗方法在目前的蛋白质治疗中， %）的患者产生中和F.IX的抑制性抗体 蛋白质活性使治疗无效。试图消除 通过输注高剂量的F.IX或通过免疫抑制 治疗并不总是成功的。我们假设有效的免疫 耐受性策略将使目前的血友病B治疗能够 对所有患者都有效。在本提案中，我们假设血友病B 小鼠可通过口服FIX耐受FIX。在第一个目标中， 将确定在新生儿或新生儿中是否可以实现对人FIX的口服耐受性， 成年血友病B小鼠。具体来说，我们将产生小鼠乳清酸 蛋白启动子-人因子IX转基因小鼠，并表征 hF.IX在小鼠乳中。这些转基因小鼠将用于确定 从mWAP-hF.IX雌性小鼠摄取乳汁是否能够耐受 新生血友病B小鼠对hF. IX.成年Hem B小鼠将在24小时内喂食hFIX。 他们的水，以确定是否喂养抗原的成年Hem B小鼠能够 诱导耐受性。在第二个目标中，我们将确定对人类的宽容是否 F.IX可以通过FIX在肠上皮细胞中的连续表达来实现。 血友病B小鼠。这将证明成年Hem B小鼠是否可以耐受 如果肠组织中F.IX的持续表达可能促进 诱导耐受性。

DESCRIPTION (provided by applicant): Hemophilia B is a genetic disease caused by a deficiency of clotting factor IX. Current therapy for Hemophilia B patients is protein therapy and clinical trials are currently underway for a gene therapy approach. With the current protein therapy, a small percentage (3 percent) of patients develop inhibitory antibodies that neutralize the F.IX protein activity rendering treatment ineffective. Attempts to eliminate inhibitory antibodies by infusing high doses of F.IX or by immunosuppressive treatment are not always successful. We hypothesize that effective immune tolerance strategies will enable current therapies for Hemophilia B to be successful for all patients. In this proposal we hypothesize that Hemophilia B mice can be tolerized to FIX by oral administration of FIX. In the first aim we will determine if oral tolerance to human FIX can be achieved in neonatal or adult Hemophilia B mice. Specifically, we will generate mouse whey acidic protein promoter-human Factor IX transgenic mice and characterize the levels of hF.IX in the mouse milk. These transgenic mice will be used to determine whether ingestion of milk from the mWAP-hF.IX female mice is able to tolerize the newborn Hemophilia B mice to hF.IX. Adult Hem B mice will be fed hFIX in their water to determine if feeding the antigen to adult Hem B mice is able to induce tolerance. In the second aim we will determine if tolerance to human F.IX can be achieved by continuous expression of FIX in gut epithelium of Hemophilia B mice. This will demonstrate if adult Hem B mice can be tolerized to FiX and if continuous expression of F.IX in gut tissue may facilitate the induction of tolerance.