Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA.
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA 90095, USA.
Crit Rev Immunol. 2023;43(1):13-26. doi: 10.1615/CritRevImmunol.2023047231.
Our recent studies indicated that amyotrophic lateral sclerosis (ALS) patients suffer from significantly elevated levels of interferon-gamma (IFN-γ) secretion by natural killer (NK) and CD8+ T cells, which may be responsible for the immune-pathologies seen in central nervous system and in peripheral organs of the patients. In order to counter such elevated induction of IFN-γ in patients we designed a treatment strategy to increase anti-inflammatory cytokine interleukin-10 (IL-10) by the use of probiotic strains which significantly increase the levels of IL-10. Therefore, in this paper we demonstrate disease specific functions of Al-Pro (AJ3) formulated for the adjunct treatment of auto-immune diseases including ALS, and compared the function with CA/I-Pro (AJ4) for the treatment of cancer and viral diseases, and NK-CLK (AJ2) for maintenance of immune balance and promotion of disease prevention. The three different formulations of probiotic bacteria have distinct profiles of activation of peripheral blood mononuclear cells (PBMCs), NK, and CD8+ T cells, and their induced activation is different from those mediated by either IL-2 or IL-2 + anti-CD16 monoclonal antibodies (mAbs) or IL-2 + anti-CD3/CD28 mAbs. IL-2 + anti-CD16 mAb activation of PBMCs and NK cells had the highest IFN-γ/IL-10 ratio, whereas IL-2 combination with sAJ4 had the next highest followed by IL-2 + sAJ2 and the lowest was seen with IL-2 + sAJ3. Accordingly, the highest secretion of IFN-γ was seen when the PBMCs and NK cells were treated with IL-2 + sAJ4, intermediate for IL-2 + sAJ2 and the lowest with IL-2 + sAJ3. The levels of IFN-γ induction and the ratio of IFN-γ to IL-10 induced by different probiotic bacteria formulation in the absence of IL-2 treatment remained much lower when compared to those treated in the presence of IL-2. Of note is the difference between NK cells and CD8+ T cells in which synergistic induction of IFN-y by IL-2 + sAJ4 was significantly higher in NK cells than those seen by CD8+ T cells. Based on these results, sAJ3 should be effective in alleviating auto-immunity seen in ALS since it will greatly regulate the levels and function of IFN-γ negatively, decreasing overactivation of cytotoxic immune effectors and prevention of death in motor neurons.
我们最近的研究表明，肌萎缩侧索硬化症（ALS）患者的自然杀伤（NK）和 CD8+T 细胞分泌的干扰素-γ（IFN-γ）水平显著升高，这可能是导致患者中枢神经系统和外周器官免疫病理学的原因。为了对抗患者中这种 IFN-γ的过度诱导，我们设计了一种治疗策略，通过使用益生菌菌株来增加抗炎细胞因子白细胞介素-10（IL-10）的水平，这些益生菌菌株能显著增加 IL-10 的水平。因此，在本文中，我们证明了 Al-Pro（AJ3）针对自身免疫性疾病（包括 ALS）的辅助治疗的特定疾病功能，并将其功能与 CA/I-Pro（AJ4）用于癌症和病毒疾病的治疗以及 NK-CLK（AJ2）用于维持免疫平衡和促进疾病预防进行了比较。三种不同配方的益生菌具有不同的外周血单核细胞（PBMC）、NK 和 CD8+T 细胞激活特征，其诱导的激活与 IL-2 或 IL-2+抗 CD16 单克隆抗体（mAb）或 IL-2+抗 CD3/CD28 mAb 介导的激活不同。IL-2+抗 CD16 mAb 对 PBMC 和 NK 细胞的激活具有最高的 IFN-γ/IL-10 比值，而 IL-2 与 sAJ4 的组合次之，IL-2+sAJ2 再次之，IL-2+sAJ3 最低。因此，当用 IL-2+sAJ4 处理 PBMC 和 NK 细胞时，观察到 IFN-γ 的分泌最高，中间是用 IL-2+sAJ2 处理，最低是用 IL-2+sAJ3 处理。与在 IL-2 存在下处理的情况相比，在没有 IL-2 处理的情况下，不同益生菌细菌配方诱导的 IFN-γ 诱导水平和 IFN-γ/IL-10 比值仍然低得多。值得注意的是 NK 细胞和 CD8+T 细胞之间的差异，其中 IL-2+sAJ4 协同诱导的 IFN-y 在 NK 细胞中比在 CD8+T 细胞中高得多。基于这些结果，sAJ3 应该能有效缓解 ALS 中自身免疫的发生，因为它将极大地负调控 IFN-γ 的水平和功能，减少细胞毒性免疫效应物的过度激活，并防止运动神经元死亡。
