Department of Immunology & Inflammation, Centre for Inflammatory Disease, Imperial College London, London, UK.
Imperial College Healthcare NHS Trust, London, UK.
Sci Rep. 2022 Feb 28;12(1):3330. doi: 10.1038/s41598-022-06413-2.
Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.
抗体介导的排斥反应是肾移植失败的主要原因。循环中预先形成的供体特异性抗体（DSA）可能是由于输血、妊娠或先前的移植而产生的。由于部分或暂时有效、不良反应或患者不适合，目前的治疗策略受到限制。以前探索自身免疫性疾病的体内研究表明，脾酪氨酸激酶（SYK）信号在致病性自身抗体的产生中起作用。SYK 在同种异体抗体产生中的作用尚不清楚，我们在通过将 F344 全血输注到 LEW 大鼠中建立的致敏啮齿动物模型中对此进行了研究。用选择性 SYK 抑制剂 fostamatinib 对致敏大鼠进行 2 周的治疗强烈阻断了循环 DSA 的产生，而不影响总免疫球蛋白水平，并且抑制作用可持续至治疗方案完成后 5 周。Fostamatinib 治疗并未影响成熟 B 细胞亚群或浆细胞水平，未治疗对照、载体处理和 fostamatinib 处理动物之间的水平相似。我们的数据表明，在等待肾移植期间，对于有输血后致敏风险的患者，fostamatinib 可能提供一种替代治疗选择。
