A Synthetic Live Attenuated Bacterial Vaccine for Countering Autoimmune Disease

Immunotherapy has led to impressive advances in the treatment of human diseases, including autoimmune disorders; yet, its clinical outcomes remain limited by various factors, including the subversive effects of pro-inflammatory environments, and the fact that the key molecular determinants of immune tolerance remain elusive. Recently, significant interest in exploiting live attenuated bacterial strains for addressing human diseases has emerged. However, relatively few examples of the application of such vaccines for addressing rheumatoid arthritis have been reported. Here, we describe a synthetic, metabolically engineered, live attenuated vaccine strain of Brucella melitensis (Bm) that expresses natural compounds (indoles) that reduce tissue inflammation, polarize M2 macrophages (Mφ), promote regulatory T cell (T_reg) activation, and reduce expression of pro-inflammatory cytokines. Strikingly, a combined treatment of the synthetic vaccine with an adoptive cell transfer (ACT) of regulatory T cells (T_regs) significantly enhanced the accumulation of M2 Mφ and T_reg persistence in the inflamed tissues, resulting in the suppression of the development of autoimmune arthritis. Taken together, this work defines a novel strategy to reinforce immunotherapy against autoimmune disorders such as rheumatoid arthritis (RA), and provides new therapeutic prospects for improving immunotherapy for autoimmune disorders.