Factor IX administration in the skin primes inhibitor formation and sensitizes hemophilia B mice to systemic factor IX administration.
Factor IX administration in the skin primes inhibitor formation and sensitizes hemophilia B mice to systemic factor IX administration.
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DOI：
10.1016/j.rpth.2023.102248
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发表时间：
2023-11
影响因子：
4.6
通讯作者：
Kaczmarek, Radoslaw
中科院分区：
文献类型：
--
作者：
Sherman, Alexandra;Bertolini, Thais B.;Arisa, Sreevani;Herzog, Roland W.;Kaczmarek, Radoslaw
因子IX抑制剂的形成是出血性疾病B型血友病替代疗法中最严重的并发症，高达60%的抑制剂患者发生严重的过敏反应加剧了这种并发症。B型血友病免疫耐受诱导治疗成功率低，需要寻找新的免疫耐受治疗方法。皮肤相关淋巴组织已成功靶向过敏原特异性免疫治疗。我们的目标是开发一种基于皮内给药FIX的预防性免疫耐受方案，以防止替代治疗后抑制剂的形成和/或过敏反应。在C3H/HeJ血友病B小鼠中，我们使用Bethesda法和酶联免疫吸附法测量FIX抑制剂、抗FIX免疫球蛋白G1和免疫球蛋白E滴度，在每周两次皮内注射FIX或FIX- fc 4周后，每周全身注射FIX 5至6周。我们还测量了单次或多次皮内注射FIX后皮肤引流淋巴结中皮肤抗原呈递、滤泡辅助性T和生发中心B细胞的频率。皮内给药与全身给药相比增强FIX抑制剂的形成。我们进一步发现，即使在0.4 IU/kg的低剂量下，单独皮内给药也会触发抑制剂的形成，这比在血友病B小鼠中诱导抑制剂形成通常需要的40 IU/kg的静脉注射剂量低100倍。此外，皮内给药触发皮肤引流淋巴结生发中心的形成，并使小鼠对全身给药敏感。因子IX-Fc融合蛋白不调节抑制剂的形成。皮内给药具有高度的免疫原性，表明皮肤隔室不适应免疫耐受诱导或治疗性输送凝血因子。因子IX抑制剂患者迫切需要更好的免疫耐受治疗。我们尝试通过在B型血友病小鼠皮肤中施用FIX或FIX- fc诱导耐受性。在皮肤中施用FIX或FIX- fc比全身注射更具免疫原性。皮肤不适应对FIX的耐受性诱导或治疗性递送。
Factor IX inhibitor formation is the most serious complication of replacement therapy for the bleeding disorder hemophilia B, exacerbated by severe allergic reactions occurring in up to 60% of patients with inhibitors. Low success rates of immune tolerance induction therapy in hemophilia B necessitate the search for novel immune tolerance therapies. Skin-associated lymphoid tissues have been successfully targeted in allergen-specific immunotherapy. We aimed to develop a prophylactic immune tolerance protocol based on intradermal administration of FIX that would prevent inhibitor formation and/or anaphylaxis in response to replacement therapy. We measured FIX inhibitor, anti-FIX immunoglobulin G1, and immunoglobulin E titers using the Bethesda assay and enzyme-linked immunosorbent assay after 4 weeks of twice-weekly intradermal FIX or FIX-Fc administration followed by 5 to 6 weeks of weekly systemic FIX injections in C3H/HeJ hemophilia B mice. We also measured skin antigen-presenting, follicular helper T, and germinal center B cell frequencies in skin-draining lymph nodes after a single or repeat intradermal FIX administration. Intradermal administration enhanced FIX inhibitor formation in response to systemic administration. We further found that intradermal administration alone triggers inhibitor formation, even at a low dose of 0.4 IU/kg, which is 100-fold lower than the intravenous dose of 40 IU/kg typically required to induce inhibitor development in hemophilia B mice. Also, intradermal administration triggered germinal center formation in skin-draining lymph nodes and sensitized mice to systemic administration. Factor IX–Fc fusion protein did not modulate inhibitor formation. Intradermal FIX administration is highly immunogenic, suggesting that the skin compartment is not amenable to immune tolerance induction or therapeutic delivery of clotting factors. People with factor IX inhibitors urgently need better immune tolerance therapy. We attempted tolerance induction by administering FIX or FIX-Fc in the skin of hemophilia B mice. Administration of FIX or FIX-Fc in the skin is more immunogenic than systemic injections. The skin is not amenable to tolerance induction toward or therapeutic delivery of FIX.
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影响因子：
13.8
作者：
Srinivasan A;Herzog RW;Khan I;Sherman A;Bertolini T;Wynn T;Daniell H
通讯作者：
Daniell H
影响因子：
3.9
作者：
Astermark, Jan;Holstein, Katharina;Shapiro, Amy D.
通讯作者：
Shapiro, Amy D.
影响因子：
20.3
作者：
Sherman, Alexandra;Su, Jin;Daniell, Henry
通讯作者：
Daniell, Henry
DOI：
10.1016/j.ymthe.2016.11.009
发表时间：
2017-02-01
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Herzog RW;Nichols TC;Su J;Zhang B;Sherman A;Merricks EP;Raymer R;Perrin GQ;Häger M;Wiinberg B;Daniell H
通讯作者：
Daniell H
影响因子：
7.5
作者：
Nolan, Beatrice;Klukowska, Anna;Liesner, Raina
通讯作者：
Liesner, Raina