title: 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 caused by immune-mediated damage of myelin sheath. Current therapies aim to block such immune responses. However, this blocking is not sufficiently specific and hence compromises immunity, leading to severe side effects. In addition, blocking medications usually provide transient effects and require frequent administration, which further increases the chance to compromise immunity. In this regard, myelin-specific therapy may provide the desired specificity and a long-lasting therapeutic effect by inducing myelin-specific regulatory T (Treg) cells. Tolerogenic dendritic cells (TolDCs) are one such therapy. However,ex vivogenerated TolDCs may be converted into immunogenic DCs in a proinflammatory environment. In this study, we identified a potential novel myelin-specific therapy that works with immunogenic DCs, hence without thein vivoconversion concern. We showed that immunization with DCs, engineered to overexpress 25-hydroxyvitamin D 1α-hydroxylase forde novosynthesis of a focally high 1,25-dihydroxyvitamin D concentration in the peripheral lymphoid tissues, induced Tregcells. In addition, such engineered DCs, when pulsed with a myelin antigen, led to myelin-specific suppression of ongoing experimental allergic encephalomyelitis (an MS animal model), and the disease suppression depended on forkhead-box-protein-P3(foxp3)+Tregcells. Our data support a novel concept that immunogenic DCs can be engineered for myelin-specific therapy for MS.-Li, C.-H., Zhang, J., Baylink, D. J., Wang, X., Goparaju, N. B., Xu, Y., Wasnik, S., Cheng, Y., Berumen, E. C., Qin, X., Lau, K.-H. W., Tang, X. 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.
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.|Department of Emergency Medicine, Chang-Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.|Graduate Institute of Clinical Medical Sciences, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Huang
authors.initials: CH
authors.lastname: Li
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.|Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Henan, China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Baylink
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.|Division of Infectious Disease, Jinan Infectious Disease Hospital, Shandong University, Jinan, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Naga Bharani
authors.initials: NB
authors.lastname: Goparaju
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Samiksha
authors.initials: S
authors.lastname: Wasnik
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.|Yue Yang Hospital of Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Edmundo Carreon
authors.initials: EC
authors.lastname: Berumen
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.|Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, USA.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Qin
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.|Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, USA.
authors.forename: Kin-Hing William
authors.initials: KW
authors.lastname: Lau
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA; xitang@llu.edu.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Tang
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D000941:Antigens; D001854:Bone Marrow Cells; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D008221:Lymphoid Tissue; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D000941:Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
keywords: 1,25(OH)2D, foxp3; Treg; multiple sclerosis; regulatory T cells