Studies citing vitamin D deficiency associated with rheumatoid arthritis (RA) have indicated that vitamin D supplementation might reduce the risk of or enhance therapeutic approaches to treat this disease. The discovery of a new secosteroidogenic pathway initiated by P450scc that produces vitamin D3 hydroxyderivatives has opened new options in treatment for RA. This first and main product of the pathway, 20(OH)D3, is non-toxic at concentrations as high as 30?g/kg. We have approached the molecular pathogenesis of RA under the thesis that RA is an autoimmune disorder characterized by T cell dysregulation and that the use of vitamin D analogs can enhance the immunomodulatory effects of T cells. For example, T cells activated by altered peptide ligand (APL) peptide of the immunodominant epitope of type II collagen (CII), ie A9, CII245-270 (A260, B261, N263), upregulate the expression of the vitamin D receptor (VDR) so that both 1,25(OH)2D3 and 20(OH)D3 enhance the suppression of the inflammatory responses by inhibiting Th1 and Th17 responses while increasing the production of Th2 cytokines and IL- 10. We feel that the net result of combining therapies with both analog peptides and vitamin D will be a synergistic downregulation of the severity of arthritis at lower and safer doses than either therapy alone. Yet the mechanism of this suppression remains unknown. Our central hypothesis is that T inhibitory cells induced by the APL upregulate the Vitamin D receptor (VDR) allowing vitamin D3 to act directly on T cells to enhance both the suppression of inflammatory cytokines and the secretion of Th2/regulatory cytokines ultimately leading to suppression of autoimmune arthritis;and that the non-calcemic 20(OH)D3, will be as effective and less toxic than the classical form of vitamin D3 [1,25(OH) 2D3]. To understand the mechanism by which vitamin D enhances this response we propose the following specific aims:
Aim 1) To test the hypothesis that redirecting the T cell cytokine profile is a mechanism by which 20(OH)D3 enhances the effectiveness of an APL in attenuating collagen-induced arthritis, Aim 2) To test the hypothesis that modulation of autoimmune arthritis can be enhanced by combining two interventions[ 20(OH)D3 and an APL], and Aim 3) To test the hypothesis that 20(OH)D3 intersects the alternate T cell signaling pathway and affects APL driven T cell cytokine production. Successful completion of these experiments will demonstrate if vitamin D and analog peptides work in synergy to suppress autoimmune arthritis and whether the noncalcemic form of vitamin D, 20(OH)D3 is as effective as 1,25(OH)2D3.
The significance of the proposed work lies with the parallel use of arthritis-prone mice to introduce a new treatment strategy for RA. In this application, we plan to use the collagen- induced arthritis model to study the mechanism of synergy between a new safer hydroxyderivative of vitamin D3 (20(OH) D3 and an altered peptide ligand of type II collagen. The purpose of the proposal is to delineate the mechanism of action of this combined therapy with the ultimate aim of developing safer and more effective treatments for RA.