Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. AJI-100 significantly reduces the frequency of skin-homing CLA⁺ donor T cells, limiting allograft invasion and tissue destruction by T effectors. AJI-100 also suppresses pathogenic Th1 and Th17 cells in the spleen yet spares beneficial regulatory T cells. We show dual JAK2/Aurora kinase A blockade enhances human type 2 innate lymphoid cell (ILC2) responses, which are capable of tissue repair. ILC2 differentiation mediated by GATA3 requires STAT5 phosphorylation (pSTAT5) but is opposed by STAT3. Further, we demonstrate that Aurora kinase A activation correlates with low pSTAT5 in ILC2s. Importantly, AJI-100 maintains pSTAT5 levels in ILC2s by blocking Aurora kinase A and reduces interference by STAT3. Therefore, combined JAK2/Aurora kinase A inhibition is an innovative strategy to merge immune suppression with tissue repair after transplantation.

中文翻译：

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双重 JAK2/Aurora 激酶 A 抑制通过同种异体失活和 ILC2 介导的组织修复防止人类皮肤移植物排斥

预防同种异体移植物排斥通常需要终生免疫抑制，这有可能导致宿主免疫力受到广泛损害。宿主 T 细胞功能的非选择性抑制会增加接受者发生机会性感染和继发性恶性肿瘤的风险。在这里，我们证明 AJI-100 是 JAK2 和极光激酶 A 的双重抑制剂，可改善人类 T 细胞对皮肤移植物的排斥反应并提供持久的同种异体失活。^{AJI-100 显着降低皮肤归巢 CLA +}的频率供体 T 细胞，限制 T 效应器对同种异体移植物的侵袭和组织破坏。AJI-100 还抑制脾脏中的致病性 Th1 和 Th17 细胞，同时保留有益的调节性 T 细胞。我们显示双重 JAK2/Aurora 激酶 A 阻断增强了人类 2 型先天性淋巴样细胞 (ILC2) 反应，它能够进行组织修复。GATA3 介导的 ILC2 分化需要 STAT5 磷酸化 (pSTAT5)，但与 STAT3 相反。此外，我们证明极光激酶 A 激活与 ILC2 中的低 pSTAT5 相关。重要的是，AJI-100 通过阻断 Aurora 激酶 A 并减少 STAT3 的干扰来维持 ILC2 中的 pSTAT5 水平。因此，联合 JAK2/Aurora 激酶 A 抑制是一种将免疫抑制与移植后组织修复相结合的创新策略。