The VDR is expressed in most cells of the immune system, including T lymphocytes, and antigen-presenting cells (APC) such as macrophages and dendritic cells. Growing evidence indicates that 1,25(OH)2D3 is a modulator of immune system function, consistent with its capacity to control cellular differentiation. Helper T (Th) cells are central to all antigen- specific immune responses. The microenvironment in which naive Th cells develop determines which of 2 subtypes predominates (Th1 or Th2). Th1 and Th2 cells are direct targets of 1,25(OH)2D3. Quiescent CD4+ T cells expressed VDRs but only at low concentrations, which increased 5-fold after activation. 1,25(OH)2D3 decreased the proliferation of purified Th cells and decreased the production of IFN-y, IL-2, and IL-5. In Th2 cells, 1,25(OH)2D3 increased the production of IL- 4. The effectiveness of 1,25(OH)2D3 for suppression of autoimmune diseases in vivo has been shown to depend on IL-2 and IL-4 secretion. CD4+ T cells from VDR knockout (KO) mice (which do not respond to vitamin D) produced more IFN-y and less IL-2, IL-4, and IL-5 than did CD4+ T cells from wild-type (WT) mice. Consistent with this finding, in vivo antigen stimulation of VDR KO mice resulted in increased antigen-specific IFN-y response. Furthermore the mixed lymphocyte reaction with CD4+ T cells from VDR KO mice was twice that with CD4+ T cells from WT mice. The data suggest that T cells from VDR KO mice secrete more IFN-y and less of the Th2 cytokines IL-4 and IL-5. Furthermore, 1,25(OH)2D3 reduced Th1 cell-associated cytokine production and increased Th2 cell IL-4 secretion. In the absence of vitamin D signaling, the T cell compartment has a potentially stronger Th1 phenotype.
One study of mice in which the VDR gene had been ablated concluded that altered immune responses were an indirect consequence of VDR disruption because they could be restored by normalization of calcium homeostasis. However, another study revealed abnormal development of pro-inflammatory T helper 1 (Th1) cell development in VDR knockout mice. Moreover, mice rendered 1,25(OH)2D3 deficient by knockout of the gene encoding 25-hydroxyvitamin D3 1-a-hydroxylase were deficient in peripheral T lymphocytes.
These findings help to provide a molecular basis for the therapeutic potential of 1,25(OH)2D3 analogues in treatment Th1- stimulated autoimmune diseases. Indeed, in mice, 1,25(OH)2D3 can prevent systemic lupus erythematosus, experimental autoimmune encephalomyelitis (EAE), collagen- induced arthritis, inflammatory bowel disease and autoimmune diabetes (96). For example, treatment of mice with myelin basic protein induces EAE, a multiple sclerosis-like disease whose progression is driven by activated T cells. Dietary 1,25(OH)2D3 prevented the onset of EAE and the progression of established disease (99, 100). The most firmly established clinical use of 1,25(OH)2D3 analogues is in the treatment of the Th1-driven chronic inflammatory skin disease psoriasis, which affects 2% of the population. 1,25(OH)2D3 analogues account for 50% of all drugs used to treat mild to moderate disease. Analogues are used topically, and one of the most throughly tested is the secosteroidal compound calcipotriol, which is effective either alone or when administered in combination with anti- inflammatory steroids. Going without your pills? Buy cheap online pharmacy generic drugs