Tolerogenic Dendritic Cells Induced by Vitamin D Receptor Ligands Enhance Regulatory T Cells Inhibiting Autoimmune Diabetes

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Abstract
Abstract: Dendritic cells (DCs) not only induce but also modulate T cell activation. 1,25‐Dihydroxyvitamin D3 [1,25‐(OH)2D3] induces DCs with a tolerogenic phenotype, characterized by decreased expression of CD40, CD80, and CD86 co‐stimulatory molecules, low IL‐12, and enhanced IL‐10 secretion. We have found that a short treatment with 1,25‐(OH)2D3 induces tolerance to fully mismatched mouse islet allografts, and that this tolerance is stable to challenge with donor‐type spleen cells and allows acceptance of donor‐type vascularized heart grafts. This effect is enhanced by co‐administration of mycophenolate mofetil (MMF), a selective inhibitor of T and B cell proliferation, that also has effects similar to 1,25‐(OH)2D3 on DCs. Graft acceptance is associated with impaired development of type 1 CD4+ and CD8+ cells and an increased percentage of CD4+CD25+ regulatory cells expressing CD152 in the spleen and in the draining lymph node. Transfer of CD4+CD25+ cells from tolerant mice protects 100% of the syngeneic recipients from islet allograft rejection. CD4+CD25+ cells that are able to inhibit the T cell response to a pancreatic autoantigen and to significantly delay disease transfer by pathogenic CD4+CD25− cells are also induced by treatment of adult nonobese diabetic (NOD) mice with a selected vitamin D receptor (VDR) ligand. This treatment arrests progression of insulitis and Th1 cell infiltration, and inhibits diabetes development at non‐hypercalcemic doses. The enhancement of CD4+CD25+ regulatory T cells able to mediate transplantation tolerance and to arrest type 1 diabetes development by a short oral treatment with small organic compounds that induce tolerogenic DCs, like VDR ligands, suggests possible clinical applications of this approach.

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