TY - JOUR
T1 - Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D3
AU - Mattner, Frank
AU - Smiroldo, Simona
AU - Galbiati, Francesca
AU - Muller, Marc
AU - Di Lucia, Pietro
AU - Poliani, Pietro L.
AU - Martino, Gianvito
AU - Panina-Bordignon, Paola
AU - Adorini, Luciano
PY - 2000
Y1 - 2000
N2 - 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits production of IL-12, a cytokine involved in the development of Th1 cells and in the pathogenesis of Th1-mediated autoimmune diseases. Here, we show that 1,25(OH)2D3 and a non-hypercalcemic analogue are selective and potent inhibitors of Th1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype. Administration of 1,25(OH)2D3 or its analogue prevents chronic-relapsing experimental allergic encephalomyelitis (CR-EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG35-55) in Biozzi AB/H mice. The inhibition of EAE induction is associated with a profound reduction of MOG35-55-specific proliferation and Th1 cell development. Importantly, the non-hypercalcemic analogue also provides long-term protection from EAE relapses induced by immunization with spinal cord homogenate when administered for a short time at symptom onset or even after the first peak of disease. Neuropathological analysis shows a reduction of inflammatory infiltrates, demyelinated areas and axonal loss in brains and spinal cords of treated mice. These resuls indicate that inhibition of IL-12-dependent Th1 cell development is associated with effective treatment of CR-EAE and suggest the feasibility of an approach based on low molecular weight inhibitors of IL-12 production in the treatment of multiple sclerosis.
AB - 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits production of IL-12, a cytokine involved in the development of Th1 cells and in the pathogenesis of Th1-mediated autoimmune diseases. Here, we show that 1,25(OH)2D3 and a non-hypercalcemic analogue are selective and potent inhibitors of Th1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype. Administration of 1,25(OH)2D3 or its analogue prevents chronic-relapsing experimental allergic encephalomyelitis (CR-EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 (MOG35-55) in Biozzi AB/H mice. The inhibition of EAE induction is associated with a profound reduction of MOG35-55-specific proliferation and Th1 cell development. Importantly, the non-hypercalcemic analogue also provides long-term protection from EAE relapses induced by immunization with spinal cord homogenate when administered for a short time at symptom onset or even after the first peak of disease. Neuropathological analysis shows a reduction of inflammatory infiltrates, demyelinated areas and axonal loss in brains and spinal cords of treated mice. These resuls indicate that inhibition of IL-12-dependent Th1 cell development is associated with effective treatment of CR-EAE and suggest the feasibility of an approach based on low molecular weight inhibitors of IL-12 production in the treatment of multiple sclerosis.
KW - Chronic-relapsing experimentall allergic encephalomyelitis
KW - Th1
KW - Vitamin D
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U2 - 10.1002/1521-4141(200002)30:2<498::AID-IMMU498>3.0.CO;2-Q
DO - 10.1002/1521-4141(200002)30:2<498::AID-IMMU498>3.0.CO;2-Q
M3 - Article
C2 - 10671205
AN - SCOPUS:0033975024
VL - 30
SP - 498
EP - 508
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 2
ER -