The active form of vitamin D sub(3), 1,25(OH) sub(2)D sub(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) sub(2)D sub(3) are reflected by a strong potency to prevent onset and even recurrence of autoimmune diseases. A major limitation in using 1,25(OH) sub(2)D sub(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) sub(2)D sub(3)) is a structural 1,25(OH) sub(2)D sub(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) sub(2)D sub(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) sub(2)D sub(3) 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. copyright 2002 Wiley-Liss, Inc.
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.
Prevention of type 1 diabetes in NOD mice by 1,25-dihydroxyvitamin D3 1alpha,25(OH)2D3 is accompanied by a T-helper (Th) 1/Th2 cytokine shift in the pancreas. The aim of this study was to investigate ...whether this immune shift also occurs outside of the pancreas and whether it is limited to autoantigen-specific immune responses. NOD mice treated with 1alpha,25(OH)2D3 (5 microg/kg every 2 days) or control vehicle were immunized with GAD65 (p524-543) or ovalbumin (OVA) in the rear footpads. First, we examined T-cell proliferation and cytokine production (via enzyme-linked immunosorbent assay) of draining lymph node cells in vitro with or without peptide rechallenge. Although no differences in proliferation were measured between control and 1alpha,25(OH)2D3-treated mice after in vitro GAD65 rechallenge, a marked shift in cytokine secretion profile was seen in 1alpha,25(OH)2D3-treated mice: interleukin-4 was increased (37 +/- 5 vs. 21 +/- 12 pg/ml in controls, P < 0.005), whereas gamma-interferon levels were decreased (6 +/- 3 vs. 9 +/- 3 ng/ml in controls, P < 0.05). This shift was absent in OVA-primed mice. Second, we measured cytokine profiles by reverse transcriptase-polymerase chain reaction in popliteal lymph nodes at different time points after priming with GAD65 or OVA in vivo. A marked Th1/Th2 shift occurred in 1alpha,25(OH)2D3-treated mice after in vivo priming with GAD65. Again, this shift was absent after OVA immunization. Finally, we measured cytokine profiles after rechallenge with a panel of autoantigens (GAD65, heat shock protein 65, insulin B-chain) and control antigens (OVA, keyhole limpet hemocyanine, myelin proteolipid protein, tetanus toxin) and confirmed the Th1/Th2 shift in autoantigen-injected mice but not in control antigen-injected mice. In conclusion, the immune deviation induced by 1alpha,25(OH)2D3 in NOD mice can also be induced in the peripheral immune system but is limited to pancreatic autoantigens.
