title: Targeted 25-hydroxyvitamin D3 1α-hydroxylase adoptive gene therapy ameliorates dss-induced colitis without causing hypercalcemia in mice.
abstract: Systemic 1,25(OH)2D3 treatment ameliorating murine inflammatory bowel diseases (IBD) could not be applied to patients because of hypercalcemia. We tested the hypothesis that increasing 1,25(OH)2D3 synthesis locally by targeting delivery of the 1α-hydroxylase gene (CYP27B1) to the inflamed bowel would ameliorate IBD without causing hypercalcemia. Our targeting strategy is the use of CD11b(+)/Gr1(+) monocytes as the cell vehicle and a macrophage-specific promoter (Mac1) to control CYP27B1 expression. The CD11b(+)/Gr1(+) monocytes migrated initially to inflamed colon and some healthy tissues in dextran sulfate sodium (DSS) colitis mice; however, only the migration of monocytes to the inflamed colon was sustained. Adoptive transfer of Gr1(+) monocytes did not cause hepatic injury. Infusion of Mac1-CYP27B1-modified monocytes increased body weight gain, survival, and colon length, and expedited mucosal regeneration. Expression of pathogenic Th17 and Th1 cytokines (interleukin (IL)-17a and interferon (IFN)-α) was decreased, while expression of protective Th2 cytokines (IL-5 and IL-13) was increased, by the treatment. This therapy also enhanced tight junction gene expression in the colon. No hypercalcemia occurred following this therapy. In conclusion, we have for the first time obtained proof-of-principle evidence for a novel monocyte-based adoptive CYP27B1 gene therapy using a mouse IBD model. This strategy could be developed into a novel therapy for IBD and other autoimmune diseases.
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Baylink
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Walter
authors.affiliation: 1] Department of Medicine, Loma Linda University, Loma Linda, California, USA [2] Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, USA.
authors.forename: Kin-Hing William
authors.initials: KH
authors.lastname: Lau
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Xianmei
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Department of Medicine, Loma Linda University, Loma Linda, California, USA [2] Department of Medicine, Lviv State College of Physical Culture, Lviv, Ukraine.
authors.forename: Andriy
authors.initials: A
authors.lastname: Cherkas
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Tang
authors.affiliation: 1] Department of Medicine, Loma Linda University, Loma Linda, California, USA [2] Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, California, USA.
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Qin
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D019264:Adoptive Transfer; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006934:Hypercalcemia / Q000209:etiology; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019076:Transgenes
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; C480309:Ly6G antigen, mouse; D016177:Macrophage-1 Antigen; D016264:Dextran Sulfate; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase