Development of a stable autologous regulatory T cell-based cell therapy for multiple sclerosis

Abstract

In autoimmune diseases, FOXP3 + regulatory T cells (Tregs) skew towards a pro-inflammatory, non-suppressive phenotype and are unable to control the exaggerated autoimmune responses. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Our recent findings provide for the first time evidence that the inflamed blood-brain barrier (BBB) affects human Treg stability. Using functional in vitro assays, we found that the suppressive capacity of migrated Tregs was affected. Transcriptome analysis indicated that migrated human Tregs of healthy donors and MS patients are less suppressive, have a pro-inflammatory Th1/17 signature and upregulate the mTOR signaling pathway. In vitro treatment of migrated Tregs with the clinically-approved mTOR inhibitor rapamycin restored the loss of suppressive function. In MS-derived Tregs specifically, Th17-related pathways were increased while amphiregulin was downregulated. This suggests a pre-existing susceptibility towards inflammation and lost regenerative capacity in MS-derived migrated Tregs. These insights and specific target identification can help in significantly improving the efficacy of autologous Treg therapy of MS. The aim is to target this BBB-induced Treg instability in patient-derived Tregs by genetic manipulation. By this, we restore and stabilize their immunosuppressive and regenerative function and use these designer Tregs as a powerful, autologous cell therapy for MS.