Expansion of immature, nucleated red blood cells by transient low‐dose methotrexate immune tolerance induction in mice,Clinical & Experimental Immunology

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Expansion of immature, nucleated red blood cells by transient low‐dose methotrexate immune tolerance induction in mice
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2020-11-18 , DOI: 10.1111/cei.13552
J Q Tran ₁ , D Grover ₁ , M Zhang ₂ , M Stapels ₃ , R Brennan ₄ , D S Bangari ₅ , P A Piepenhagen ₅ , E Roberts ₅ , P Oliva ₁ , F Zubair ₁ , J L Vela ₁ , S M Richards ₆ , A M Joseph ₁

Affiliation

Biological treatments such as enzyme‐replacement therapies (ERT) can generate anti‐drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low‐dose methotrexate (TLD‐MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long‐lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD‐MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high‐risk, cross‐reactive immunological material (CRIM)‐negative infantile‐onset Pompe disease (IOPD) patients. More recently, evaluation of TLD‐MTX demonstrated benefit in CRIM‐positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD‐MTX, non‐targeted transcriptional and proteomic screens were conducted and revealed up‐regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter‐119⁺CD71⁺ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD‐MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.

中文翻译：

通过瞬时低剂量甲氨蝶呤免疫耐受诱导小鼠扩增未成熟有核红细胞

酶替代疗法 (ERT) 等生物治疗可以产生抗药物抗体 (ADA)，这可能会降低药物疗效并影响患者安全，因此引发了减轻 ADA 反应的研究。瞬时低剂量甲氨蝶呤 (TLD-MTX) 作为预防性 ITI 方案，与 ERT 同时给药时，可在小鼠体内诱导 ADA 长期还原为重组人阿葡萄糖苷酶α (rhGAA)。在目前的临床实践中，包括 TLD-MTX、利妥昔单抗和静脉注射免疫球蛋白（可选）在内的预防性 ITI 方案，成功诱导高风险、交叉反应性免疫物质 (CRIM) 阴性婴儿发病庞贝氏症患者对 rhGAA 进行 ADA 的持久控制疾病（IOPD）患者。最近，TLD-MTX 的评估表明对 CRIM 阳性 IOPD 患者有益。为了更清楚地了解 TLD-MTX 的有效性机制，进行了非靶向转录和蛋白质组筛选，并揭示了红细胞生成特征的上调。验证性研究显示，脾脏的重量暂时变大，脾脏细胞结构增加，并且在骨髓和血液中成熟红细胞 (RBC) 最初减少后，在脾脏和血液中观察到 Ter-119 ⁺ CD71 ⁺未成熟红细胞显着扩张。老鼠的血。组织学切片显示这些小鼠的脾红髓中的有核细胞增加，包括造血前体细胞。这项研究表明，在免疫耐受诱导期间，TLD-MTX 诱导血液中成熟红细胞和骨髓中未成熟红细胞短暂减少，随后脾脏和血液中未成熟有核红细胞显着富集，这表明对红细胞生成可能与诱导 rhGAA 免疫耐受有关。

更新日期：2020-11-18

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