Analogs of 1α,25‐dihydroxyvitamin D3 as pluripotent immunomodulators

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Abstract
The active form of vitamin D3, 1,25(OH)2D3, is known, besides its classical effects on calcium and bone, for its pronounced immunomodulatory effects that are exerted both on the antigen‐presenting cell level as well as directly on the T lymphocyte level. In animal models, these immune effects of 1,25(OH)2D3 are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases. A major limitation in using 1,25(OH)2D3 in clinical immune therapy are the adverse side effects on calcium and on bone. TX527 (19‐nor‐14,20‐bisepi‐23‐yne‐1,25(OH)2D3) is a structural 1,25(OH)2D3 analog showing reduced calcemic activity associated with enhanced in vitro and in vivo immunomodulating capacity compared to the mother‐molecule. Indeed, in vitro TX527 is more potent that 1,25(OH)2D3 in redirecting differentiation and maturation of dendritic cells and in inhibiting phytohemagglutinin‐stimulated T lymphocyte proliferation. In vivo, this enhanced potency of TX527 is confirmed by a stronger potential to prevent type 1 diabetes in nonobese diabetic (NOD) mice and to prolong the survival of syngeneic islets grafts, both alone and in combination with cyclosporine A, in overtly diabetic NOD mice. Moreover, these in vivo effects of TX527 are obtained without the adverse side effects observed for 1,25(OH)2D3 itself. We believe therefore that TX527 is a potentially interesting candidate to be considered for clinical intervention trails in autoimmune diseases. J. Cell. Biochem. 88: 223–226, 2003.