Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX, USA.
Department of Entomology, Texas A&M University, College Station, Bryan, TX, USA.
Gut Microbes. 2022 Jan-Dec;14(1):2143222. doi: 10.1080/19490976.2022.2143222.
Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., 16M ∆, Bm∆) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T (T) cells. We demonstrated that treatment with Bm∆ polarized macrophages (Mφ) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted T function; moreover, when combined with adoptive cell transfer (ACT) of T cells, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity, and reducing inflammation by remodeling the IME and augmenting T cell function.
免疫疗法在治疗自身免疫和炎症性疾病方面取得了令人瞩目的进展；然而，其临床疗效仍然受到多种因素的限制，包括炎症微环境 (IME)。发现有效的免疫调节药物及其控制疾病的机制，将为增强当前免疫治疗方法的效果提供创新策略。我们已经对一种减毒细菌菌株（即 16M ∆，Bm∆）进行了代谢工程改造，以产生吲哚，一种色氨酸代谢物，可控制调节性 T (T) 细胞的命运和功能。我们证明，用 Bm∆处理可使巨噬细胞 (Mφ) 极化，产生抗炎细胞因子（例如 IL-10）并促进 T 细胞功能；此外，当与 T 细胞过继细胞转移 (ACT) 结合使用时，单次使用我们工程化的细菌菌株可显著降低自身免疫性关节炎的发生率和评分，并减少关节损伤。这些发现表明，代谢工程改造的细菌如何可作为一种强大的载体，通过重塑 IME 和增强 T 细胞功能，提高免疫疗法的疗效，战胜自身免疫和减少炎症。
