title: Comparative therapeutic effects of orally administered 1,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(3) on type-1 diabetes in non-obese diabetic mice fed a normal-calcaemic diet.
abstract: Frequent injections of the hormonal form of vitamin D(3), 1,25 dihydroxyvitamin D(3) (1,25D3) reportedly inhibits autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice by correcting some of the abnormalities in antigen-presenting cells which contribute the development of pathogenic T cell responses. This route of administration greatly elevates the levels of these compounds in the bloodstream for hours after treatment, which requires mice to be fed diets formulated to contain much reduced levels of Ca to avoid the toxic effects of hypercalcaemia. In the current work, we demonstrate that feeding 1,25D3 or its synthetic precursor, 1alpha(OH) vitamin D(3) (1alphaD3), as part of a T1D supportive chow diet containing normal levels of Ca, is an effective means of reducing the incidence of disease in NOD mice, but the doses required for protection elicited hypercalcaemia. However, T1D protection elicited by D3 analogue feeding appears, at least partially, to have an immunological basis, as splenic T cells from treated mice had a decreased capacity to adoptively transfer disease. Protection is associated with an increased proportion of T cells with CD4+ forkhead box P3+ regulatory phenotype within the islet infiltrate of treated animals. The 1alphaD3 precursor is converted rapidly to the active 1,25D3 isoform in vivo. However, feeding the 1alphaD3 analogue elicited stronger T1D protection than the 1,25D3 compound, but also induced more severe hypercalcaemia. In future, the dietary supplementation of novel low-calcaemic D3 analogues may enable their continuous delivery at levels that inhibit T1D development in susceptible humans consuming normal levels of Ca.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Driver
authors.forename: O
authors.initials: O
authors.lastname: Foreman
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.forename: E
authors.initials: E
authors.lastname: van Etten
authors.forename: D V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002114:Calcinosis / Q000139:chemically induced; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D004032:Diet; D019587:Dietary Supplements; D005260:Female; D005434:Flow Cytometry; D006887:Hydroxycholecalciferols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology; D014807:Vitamin D / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014815:Vitamins / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D050071:Bone Density Conservation Agents; D006887:Hydroxycholecalciferols; D014815:Vitamins; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C008088:alfacalcidol