Maddaloni Massimo, Kochetkova Irina, Jun SangMu, Callis Gayle, Thornburg Theresa, Pascual David W
Department of Infectious Diseases & Pathology, University of Florida, Gainesville, Florida, 32611, United States of America.
Department of Microbiology & Immunology, Montana State University, Bozeman, Montana, 59717, United States of America.
PLoS One. 2015 Jan 28;10(1):e0117825. doi: 10.1371/journal.pone.0117825. eCollection 2015.
Autoimmune diseases arise from the loss of tolerance to self, and because the etiologies of such diseases are largely unknown, symptomatic treatments rely on anti-inflammatory and analgesic agents. Tolerogenic treatments that can reverse disease are preferred, but again, often thwarted by not knowing the responsible auto-antigens (auto-Ags). Hence, a viable alternative to stimulating regulatory T cells (Tregs) is to induce bystander tolerance. Colonization factor antigen I (CFA/I) has been shown to evoke bystander immunity and to hasten Ag-specific Treg development independent of auto-Ag. To translate in treating human autoimmune diseases, the food-based Lactococcus was engineered to express CFA/I fimbriae, and Lactococcus-CFA/I fermented milk fed to arthritic mice proved highly efficacious. Protection occurred via CD39+ Tregs producing TGF-β and IL-10 to potently suppress TNF-α production and neutrophil influx into the joints. Thus, these data demonstrate the feasibility of oral nutraceuticals for treating arthritis, and potency of protection against arthritis was improved relative to that obtained with Salmonella-CFA/I.
自身免疫性疾病源于对自身的耐受性丧失，由于此类疾病的病因大多不明，对症治疗依赖于抗炎和镇痛药物。能够逆转疾病的耐受性治疗是首选，但同样，往往因不知道相关的自身抗原（自身抗原）而受阻。因此，刺激调节性T细胞（Tregs）的一种可行替代方法是诱导旁观者耐受性。已证明定居因子抗原I（CFA/I）可引发旁观者免疫，并加速与自身抗原无关的抗原特异性Treg发育。为了转化应用于治疗人类自身免疫性疾病，对基于食物的乳酸乳球菌进行基因工程改造以表达CFA/I菌毛，给患关节炎的小鼠喂食乳酸乳球菌-CFA/I发酵乳证明具有高效性。保护作用通过产生转化生长因子-β（TGF-β）和白细胞介素-10（IL-10）的CD39+Tregs发生，从而有效抑制肿瘤坏死因子-α（TNF-α）的产生以及中性粒细胞流入关节。因此，这些数据证明了口服营养保健品治疗关节炎的可行性，并且相对于用鼠伤寒沙门氏菌-CFA/I所获得的保护作用，对关节炎的保护效力有所提高。
