Enhancement of 1,25-dihydroxyvitamin D₃-mediated suppression of experimental autoimmune encephalomyelitis by calcitonin

Abstract

Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system characterized by inflammatory cell infiltration and subsequent demyelination of axonal tracts in the brain and spinal cord. Demyelination interferes with normal signal conduction along neuronal axons, ultimately resulting in a number of clinical symptoms including fatigue, pain, muscle weakness, and visual disturbances (1). Although the exact cause of MS remains elusive, a number of genetic and environmental factors are believed to contribute to MS susceptibility. Epidemiological studies have revealed an unusual geographical gradient for MS, in which MS incidence increases with latitude in both hemispheres (2). One potential explanation for this observation is that MS susceptibility is dependent on exposure to sunlight and the subsequent production of vitamin D (3). Consistent with this hypothesis are the findings that vitamin D supplementation and higher circulating vitamin D levels are associated with a decreased risk for MS (4, 5).Vitamin D is obtained either from production in the skin upon exposure to sunlight or through ingestion of foods containing vitamin D. Vitamin D undergoes 2 successive hydroxylation steps to form the active hormone 1␣,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], which is critical for maintaining a serum calcium level of 9-10 mg/dL for proper bone mineralization and neuromuscular function (6). A decrease in serum calcium stimulates parathyroid hormone (PTH) secretion from the parathyroid gland, leading to increased production of 1,25(OH) 2 D 3 in the kidney. PTH and 1,25(OH) 2 D 3 act in concert to effect both calcium release from bone and reabsorption of calcium in the kidney. 1,25(OH) 2 D 3 also increases intestinal calcium absorption independent of PTH, thus elevating serum calcium back to normal levels.In addition to its role in regulating serum calcium levels, vitamin D acts as an important immune system modulator. The vitamin D receptor is present in a number of different immune cell types, including monocytes, macrophages, dendritic cells, and activated T cells (7)(8)(9). In vitro studies have demonstrated that 1,25(OH) 2 D 3 inhibits T-cell proliferation and decreases the expression of inflammatory cytokines such as IL-2 and IFN-␥ (10, 11). A number of in vivo studies have demonstrated that 1,25(OH) 2 D 3 can suppress inflammation and autoimmune pathology in a variety of animal models of autoimmune disease, including models for insulin-dependent diabetes mellitus, rheumatoid arthritis, and MS (12)(13)(14). In the experimental autoimmune encephalomyelitis (EAE) model of MS, 1,25(OH) 2 D 3 has been shown to prevent clinical signs of disease as well as to suppress disease progression (14,15). The suppressive effects of 1,25(OH) 2 D 3 appear to be closely linked to calcium. Mice on a higher calcium diet require much lower doses of 1,25(OH) 2 D 3 for disease prevention than those on a low-calcium diet (16). Moreover, complete prevention of EAE only occurs using doses of 1,25(OH) 2 D 3 that eleva...

Role of vitamin D in immune responses and autoimmune diseases, with emphasis on its role in multiple sclerosis

“…These findings suggest that vitamin D may be used for MS treatment [93] , based on the finding that complications could be prevented by vitamin D [108] . However, further studies are still needed.…”

Regulatory T cell function correlates with serum 25-hydroxyvitamin D, but not with 1,25-dihydroxyvitamin D, parathyroid hormone and calcium levels in patients with relapsing remitting multiple sclerosis

“…In experimental autoimmune encephalomyelitis (EAE), an animal-model of MS, dietary calcium intake and the subsequent elevation of serum calcium concentration were critical factors in the clinical and immunological effects of 1,25(OH) 2 D therapy [8]. Calcitonin, a protein released during hypercalcaemia, enhanced the clinical effectiveness of 1,25(OH) 2 D in EAE [9], but was not mandatory [10]. This proposed importance of calcium in EAE, led to the notice that calcium might also be a critical factor in the relationship between vitamin D and MS.…”

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

“…This eliminates the ability to properly analyze disease course by disregarding day-to-day intra-group variance, while inappropriately calculating the variance between groups, thus greatly increasing the odds of obtaining a false positive. This is also a problem in studies that utilize cumulative disease index (CDI) scoring(Becklund et al, 2009; Ochoa-Reparaz et al, 2010), in which EAE clinical scores for a group are summed over all days and then divided by the group size. The average score for each group is then plotted on a column graph and analyzed.…”