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

Abstract

The active form of vitamin D(3), 1,25(OH)(2)D(3), 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)(2)D(3) are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases. A major limitation in using 1,25(OH)(2)D(3) 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)(2)D(3)) is a structural 1,25(OH)(2)D(3) 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)(2)D(3) 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)(2)D(3) itself. We believe therefore that TX527 is a potentially interesting candidate to be considered for clinical intervention trails in autoimmune diseases.

Post–hip fracture use of prescribed calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs is associated with lower mortality: A nationwide study in Finland

“…weakness, (21) respiratory infections, (22) autoimmune diseases, (23) diabetes, (24) and cardiovascular diseases. (25) The recent literature includes a number of studies showing an association between 25-hydroxyvitamin D levels and the risk of mortality in the general population.…”

Vitamin D receptor-mediated suppression of RelB in antigen presenting cells: A paradigm for ligand-augmented negative transcriptional regulation

“…Much of this enthusiasm has arisen from a growing body of literature indicating VDR-mediated in vivo effects on T-cells and dendritic cells (DCs) that specifically inhibit Thelper type 1 (Th1) T-cell responses and may also facilitate antigen-specific tolerance [2][3][4][5][6][7][8][9][10]. Given the narrow therapeutic window for the exogenously administered native VDR ligand (1α,25-dihydroxyvitaminD 3 (1α,25(OH)D 3 )) [2,11], the eventual translation of this work from bench to bedside will depend upon the successful pursuit of one or more additional goals: (a) Identification of synthetic VDR agonists for which the in vivo potency of immune modulatory effects is uncoupled from that of other biological effects such as induction of hypercalcemia [1,5,6,11]. (b) Harnessing of the synergistic properties of VDR agonists when combined with other immunosuppressive agents [6,12].…”

The Vitamin D Analog, TX527, Promotes a Human CD4+CD25highCD127low Regulatory T Cell Profile and Induces a Migratory Signature Specific for Homing to Sites of Inflammation

“…Only the use of synthetic analogs of 1,25 (OH) 2 D 3 , in which calcemic and immunomodulatory actions have been dissociated, can lead to a possible in vivo application, topically or systemically. In this study, we explored the ability of TX527 [19-nor-14,20-bisepi-23-yne-1,25(OH) 2 D 3 ], a hypocalcemic vitamin D analog with established immunoregulatory properties (16), to directly interfere with T cell phenotype and functionality. By using a synchronized system of T cell activation, we demonstrate direct effects of TX527 on human T lymphocytes, both at the phenotypic and functional level.…”