Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury.
Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury.
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DOI：
10.1093/pnasnexus/pgad434
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发表时间：
2024-01
期刊：
影响因子：
--
通讯作者：
Mitragotri, Samir
中科院分区：
文献类型：
--
作者：
Kapate, Neha;Liao, Rick;Sodemann, Ryan Luke;Stinson, Tawny;Prakash, Supriya;Kumbhojkar, Ninad;Suja, Vineeth Chandran;Wang, Lily Li-Wen;Flanz, Mikayla;Rajeev, Rohan;Villafuerte, Dania;Shaha, Suyog;Janes, Morgan;Park, Kyung Soo;Dunne, Michael;Golemb, Bryan;Hone, Alexander;Adebowale, Kolade;Clegg, John;Slate, Andrea;McGuone, Declan;Costine-Bartell, Beth;Mitragotri, Samir
创伤性脑损伤（TBI）是一种使人衰弱的疾病，除了急性临床治疗外，目前没有其他治疗方法。虽然急性、受控的炎症对于损伤后的碎片清除和再生是重要的，但慢性、猖獗的炎症在继发性脑损伤的病理生理学中起着显著的不利作用。免疫细胞疗法由于其主动感知和迁移能力而具有独特的炎症调节治疗潜力。考虑到巨噬细胞和小胶质细胞在TBI后失调的炎症反应中的作用，巨噬细胞特别适合于这项任务。然而，维持过继转移的巨噬细胞在抗炎、伤口愈合表型中对抗促炎性TBI环境是必不可少的。为了实现这一点，我们开发了盘状微粒，称为背包，封装抗炎白细胞介素-4，和地塞米松离体巨噬细胞附着。背包持久地粘附到巨噬细胞的表面而没有内化，并且在体外7天内保持载体巨噬细胞的抗炎表型。背包-巨噬细胞疗法按比例扩大并安全地输注到皮质撞击TBI模型中的小猪中。背包-巨噬细胞迁移到脑损伤部位，减少皮质吻侧回损伤半影区小胶质细胞的促炎激活，并降低促炎生物标志物的血清浓度。这些免疫调节作用引起病变体积减少56%。据我们所知，这里报道的结果证明了细胞治疗干预在TBI的大型动物模型中的潜在用途，并突出了基于巨噬细胞的治疗的潜力。需要进一步的研究来阐明与抗炎巨噬细胞治疗相关的神经保护机制。
Traumatic brain injury (TBI) is a debilitating disease with no current therapies outside of acute clinical management. While acute, controlled inflammation is important for debris clearance and regeneration after injury, chronic, rampant inflammation plays a significant adverse role in the pathophysiology of secondary brain injury. Immune cell therapies hold unique therapeutic potential for inflammation modulation, due to their active sensing and migration abilities. Macrophages are particularly suited for this task, given the role of macrophages and microglia in the dysregulated inflammatory response after TBI. However, maintaining adoptively transferred macrophages in an anti-inflammatory, wound-healing phenotype against the proinflammatory TBI milieu is essential. To achieve this, we developed discoidal microparticles, termed backpacks, encapsulating anti-inflammatory interleukin-4, and dexamethasone for ex vivo macrophage attachment. Backpacks durably adhered to the surface of macrophages without internalization and maintained an anti-inflammatory phenotype of the carrier macrophage through 7 days in vitro. Backpack–macrophage therapy was scaled up and safely infused into piglets in a cortical impact TBI model. Backpack–macrophages migrated to the brain lesion site and reduced proinflammatory activation of microglia in the lesion penumbra of the rostral gyrus of the cortex and decreased serum concentrations of proinflammatory biomarkers. These immunomodulatory effects elicited a 56% decrease in lesion volume. The results reported here demonstrate, to the best of our knowledge, a potential use of a cell therapy intervention for a large animal model of TBI and highlight the potential of macrophage-based therapy. Further investigation is required to elucidate the neuroprotection mechanisms associated with anti-inflammatory macrophage therapy.
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影响因子：
9.3
作者：
Graber DJ;Costine BA;Hickey WF
通讯作者：
Hickey WF
影响因子：
2.9
作者：
Costine BA;Missios S;Taylor SR;McGuone D;Smith CM;Dodge CP;Harris BT;Duhaime AC
通讯作者：
Duhaime AC
影响因子：
6.2
作者：
Shih, Barbara B.;Brown, Sarah M.;Barrington, Jack;Lefevre, Lucas;Mabbott, Neil A.;Priller, Josef;Thompson, Gerard;Lawrence, Alistair B.;McColl, Barry W.
通讯作者：
McColl, Barry W.
影响因子：
2.5
作者：
Azevedo, Frederico A. C.;Carvalho, Ludmila R. B.;Herculano-Houzel, Suzana
通讯作者：
Herculano-Houzel, Suzana
影响因子：
4.1
作者：
Harting, Matthew T.;Baumgartner, James E.;Cox, Charles S.
通讯作者：
Cox, Charles S.