Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases

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 costimulatory 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 that 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 has also effects similar to 1,25(OH)₂D₃ on DCs. Graft acceptance is associated with an increased percentage of CD4⁺CD25⁺ regulatory cells in the spleen and in the draining lymph node that can protect 100% of syngeneic recipients from islet allograft rejection. CD4⁺CD25⁺ cells, 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 1,25‐dihydroxy‐16,23Z‐diene‐26,27‐hexafluoro‐19‐nor vitamin D₃ (BXL‐698). 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 VDR ligands, suggests possible clinical applications of this approach. J. Cell. Biochem. 88: 227–233, 2003.