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Abstract：
Invasive aspergillosis (IA) and mucormycosis are life-threatening diseases, especially among immunocompromised patients. Drug-resistant Aspergillus fumigatus strains have been isolated worldwide, which can pose a serious clinical problem. As IA mainly occurs in patients with compromised immune systems, the ideal therapeutic approach should aim to bolster the immune system. In this study, we focused on Vγ9Vδ2 T cells that exhibit immune effector functions and examined the possibility of harnessing this unconventional T cell subset as a novel therapeutic modality for IA. A potent antifungal effect was observed when A. fumigatus (Af293) hyphae were challenged by Vγ9Vδ2 T cells derived from peripheral blood. In addition, Vγ9Vδ2 T cells exhibited antifungal activity against hyphae of all Aspergillus spp., Cunninghamella bertholletiae, and Rhizopus microsporus but not against their conidia. Furthermore, Vγ9Vδ2 T cells also exhibited antifungal activity against azole-resistant A. fumigatus, indicating that Vγ9Vδ2 T cells could be used for treating drug-resistant A. fumigatus. The antifungal activity of Vγ9Vδ2 T cells depended on cell-to-cell contact with A. fumigatus hyphae, and degranulation characterized by CD107a mobilization seems essential for this activity against A. fumigatus. Vγ9Vδ2 T cells could be developed as a novel modality for treating IA or mucormycosis.
OBJECTIVE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.
OBJECTIVE: Invasive aspergillosis (IA) and mucormycosis are often resistant to treatment with conventional antifungal agents and have a high mortality rate. Additionally, effective antifungal treatment is hindered by drug toxicity, given that both fungal and human cells are eukaryotic, and antifungal agents are also likely to act on human cells, resulting in adverse effects. Therefore, the development of novel therapeutic agents specifically targeting fungi is challenging. This study demonstrated the antifungal activity of Vγ9Vδ2 T cells against various Aspergillus spp. and several Mucorales in vitro and discussed the mechanism underlying their antifungal activity. We indicate that adoptive immunotherapy using Vγ9Vδ2 T cells may offer a new therapeutic approach to IA.
摘要：
侵袭性曲霉病（IA）和毛霉菌病是危及生命的疾病，尤其是在免疫功能低下的患者中。已在世界范围内分离出耐药的烟曲霉菌株，这可能会带来严重的临床问题。由于IA主要发生在免疫系统受损的患者中，理想的治疗方法应该旨在增强免疫系统。在这项研究中,我们专注于表现出免疫效应功能的Vγ9Vδ2T细胞，并研究了利用这种非常规T细胞亚群作为IA新治疗方式的可能性。当来自外周血的Vγ9Vδ2T细胞攻击烟曲霉(Af293)菌丝时,观察到有效的抗真菌作用。此外,Vγ9Vδ2T细胞对所有曲霉属菌丝均具有抗真菌活性。,伯氏丘疹菌，和小孢子根霉，但不反对他们的分生孢子。此外，Vγ9Vδ2T细胞还表现出对耐药唑的烟曲霉的抗真菌活性，表明Vγ9Vδ2T细胞可用于治疗耐药的烟曲霉。Vγ9Vδ2T细胞的抗真菌活性取决于与烟曲霉菌丝的细胞间接触，以CD107a动员为特征的脱粒似乎对于这种抗烟曲霉的活性是必不可少的。可以开发Vγ9Vδ2T细胞作为治疗IA或毛霉菌病的新方法。
目的：侵袭性曲霉病（IA）和毛霉菌病通常对常规抗真菌药物治疗耐药，死亡率高。此外,有效的抗真菌治疗受到药物毒性的阻碍，鉴于真菌和人类细胞都是真核生物，抗真菌剂也可能作用于人类细胞，造成不良影响。因此,专门针对真菌的新型治疗剂的开发具有挑战性。这项研究证明了Vγ9Vδ2T细胞对各种曲霉属的抗真菌活性。和几种Mucorales在体外，并讨论了其抗真菌活性的潜在机制。我们表明使用Vγ9Vδ2T细胞的过继免疫疗法可能为IA提供新的治疗方法。
目的：侵袭性曲霉病（IA）和毛霉菌病通常对常规抗真菌药物治疗耐药，死亡率高。此外,有效的抗真菌治疗受到药物毒性的阻碍，鉴于真菌和人类细胞都是真核生物，抗真菌剂也可能作用于人类细胞，造成不良影响。因此,专门针对真菌的新型治疗剂的开发具有挑战性。这项研究证明了Vγ9Vδ2T细胞对各种曲霉属的抗真菌活性。和几种Mucorales在体外，并讨论了其抗真菌活性的潜在机制。我们表明使用Vγ9Vδ2T细胞的过继免疫疗法可能为IA提供新的治疗方法。
