Budina Erica, Reda Joseph W, Cao Shijie, Watkins Elyse A, Solanki Ani, Nguyen Mindy, Ang Phillip S, Gómez Medellín J Emiliano, Chun Hye-Rin, Foley Colleen R, Berg Brendan T K, Shim Ha-Na, Hultgren Kevin, Khosravi Zahra, Dhar Arjun, Gomes Suzana, Tremain Andrew C, Ishihara Ako, Ishihara Jun, Hubbell Jeffrey A
Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA; Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, Brooklyn, NY, USA.
Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
Cell Rep Med. 2025 Jul 15;6(7):102231. doi: 10.1016/j.xcrm.2025.102231. Epub 2025 Jul 7.
Interleukin-33 (IL-33) is an immunoregulatory cytokine that moderately suppresses experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). However, poor pharmacokinetics and toxicity hinder its clinical translation. To address these limitations, we develop an activity-attenuated IL-33 by recombinant fusion to serum albumin (SA). SA-IL-33 exhibits reduced toxicity and prolonged residence in the secondary lymphoid organs (SLOs), sites of T cell priming in autoimmunity, compared to wild-type (WT) IL-33. Prophylactic SA-IL-33 administration prevents EAE with superior efficacy to WT IL-33 and comparable efficacy to fingolimod (FTY720), a Food and Drug Administration (FDA)-approved MS drug. Therapeutic SA-IL-33 treatment also reduces disease severity in both chronic and relapsing-remitting EAE. SA-IL-33 modulates immunity in EAE by suppressing CD45 cell infiltration (including myelin-reactive T helper 17 [T17] cells) in the spinal cord, while expanding type 2 immune cells (including type 2 innate lymphoid cells [ILC2s], ST2 regulatory T cells [Tregs], T helper 2 [T2] cells, and M2-polarized macrophages) in the SLOs. These findings suggest that SA-IL-33 is a promising therapeutic for neuroinflammatory diseases.
白细胞介素-33（IL-33）是一种免疫调节细胞因子，可适度抑制实验性自身免疫性脑脊髓炎（EAE），这是一种多发性硬化症（MS）的小鼠模型。然而，其较差的药代动力学和毒性阻碍了它的临床转化。为了解决这些局限性，我们通过与血清白蛋白（SA）重组融合开发了一种活性减弱的IL-33。与野生型（WT）IL-33相比，SA-IL-33的毒性降低，并且在次级淋巴器官（SLOs）中的停留时间延长，次级淋巴器官是自身免疫中T细胞启动的部位。预防性给予SA-IL-33预防EAE的疗效优于WT IL-33，与食品药品监督管理局（FDA）批准的MS药物芬戈莫德（FTY720）相当。治疗性给予SA-IL-33还可降低慢性和复发缓解型EAE的疾病严重程度。SA-IL-33通过抑制脊髓中CD45细胞浸润（包括髓鞘反应性辅助性T细胞17 [T17]细胞）来调节EAE中的免疫反应，同时在SLOs中扩增2型免疫细胞（包括2型固有淋巴细胞[ILC2s]、ST2调节性T细胞[Tregs]、辅助性T细胞2 [T2]细胞和M2极化巨噬细胞）。这些发现表明SA-IL-33是一种有前景的神经炎症性疾病治疗药物。
