Dendritic cells, engineered to overexpress 25-hydroxyvitamin D 1α-hydroxylase and pulsed with a myelin antigen, provide myelin-specific suppression of ongoing experimental allergic encephalomyelitis

Abstract

Multiple sclerosis (MS)is causedby immune-mediated damage ofmyelin sheath.Current therapies aimto block such immuneresponses. However, this blocking is not sufficiently specific and hence compromisesimmunity, leading to severe side effects. In addition, blockingmedications usually provide transient effects and require frequent administration,which further increases the chance to compromise immunity. In this regard, myelinspecific therapymay provide the desired specificity and a long-lasting therapeutic effect by inducingmyelinspecific regulatory T (Treg) cells. Tolerogenic dendritic cells (TolDCs) are one such therapy. However, ex vivo generatedTolDCsmay be converted into immunogenicDCs in a proinflammatory environment. In this study, we identified a potential novel myelin-specific therapy that works with immunogenic DCs, hence without the in vivo conversion concern. We showed that immunization with DCs, engineered to overexpress 25-hydroxyvitamin D 1α-hydroxylase for de novo synthesis of a focally high 1,25-dihydroxyvitamin D concentration in the peripheral lymphoid tissues, induced Treg cells. In addition, such engineered DCs, when pulsed with a myelin antigen, led to myelin-specific suppression of ongoing experimental allergic encephalomyelitis (an MS animalmodel), and the disease suppression depended on forkhead-box-protein-P3(foxp3)+ Treg cells. Our data support a novel concept that immunogenic DCs can be engineered for myelin-specific therapy for MS.