1,25‐Dihydroxyvitamin D₃ acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is an incurable autoimmune neurodegenerative disease. Environmental factors may be key to MS prevention and treatment. MS prevalence and severity decrease with increasing sunlight exposure and vitamin D 3 supplies, supporting our hypothesis that the sunlight-dependent hormone, 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), inhibits autoimmune T-cell responses in MS. Moreover, 1,25-(OH) 2 D 3 inhibits and reverses experimental autoimmune encephalomyelitis (EAE), an MS model. Here, we investigated whether 1,25-(OH) 2 D 3 inhibits EAE via the vitamin D receptor (VDR) in T lymphocytes. Using bone marrow chimeric mice with a disrupted VDR only in radiosensitive hematopoietic cells or radio-resistant non-hematopoietic cells, we found that hematopoietic cell VDR function was necessary for 1,25-(OH) 2 D 3 to inhibit EAE. Furthermore, conditional targeting experiments showed that VDR function in T cells was necessary. Neither 1,25-(OH) 2 D 3 nor T-cell-specific VDR targeting influenced CD4 1 Foxp3 1 T-cell proportions in the periphery or the CNS in these studies. These data support a model wherein 1,25-(OH) 2 D 3 acts directly on pathogenic CD41 T cells to inhibit EAE.

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

“…Similarly, 1,25-(OH) 2 D 3 -treated Wt male mice had a 7-d delay in EAE onset, 50% reduced EAE incidence, 73% decreased peak severity score, and 90% less cumulative disability than placebo-treated males. These results confirmed our previous results (11,31,32,39).…”

“…In EAE, we found that 1,25-(OH) 2 D 3 did not inhibit pathogenic CD4 + T cell development or trafficking (32,33), but instead increased the sensitivity of pathogenic T cells to apoptotic signals within the CNS (33,34). These mechanisms required VDR expression in the pathogenic CD4 + T cells (11).…”

“…Spinal cord transcript isolation, reverse transcription, and real-time PCR analysis were performed as previously described (11). Oligonucleotide primers were purchased from Integrated DNA Technologies (Coralville, IA).…”

“…Abundant, diverse, and compelling evidence now supports this hypothesis (1,(8)(9)(10). The possibility that vitamin D 3 insufficiency interacts with genetic risk factors to contribute causally to MS etiology provides a strong rationale for investigating the nature and timing of the biological mechanisms involved in these interactions with a view toward preventing MS (11). Sardinia is a rare exception to the inverse correlation between ambient UV light and MS prevalence, and as such challenges the vitamin D-MS hypothesis (1).…”

Utilização da vitamina D3 e seus metabólitos na alimentação de frangos de corte sobre parâmetros imunológicos e morfometria intestinal

“…Embora vitamina D 3 atue como imunomodulador no organismo, induzindo a fusão e diferenciação de macrófagos em decorrência de um estímulo relacionado a imunidade mediada por células (Bikle et al 2008, Mayne et al 2011, os resultados para atividade fagocítica e dosagem de nitrito, indicativo da atividade dos macrófagos, não diferiram (p>0,05) com os diferentes metabólitos. perfil hematológi-co também não foi influenciado (p>0,05) pelos diferentes metabolitos da vitamina D 3 .…”