Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of Vitamin D(3), not only regulates bone and calcium metabolism but also exerts other biological activities, including immunomodulation via the nuclear Vitamin D receptor expressed in antigen-presenting cells and activated T cells. This regulation is mediated through interference with nuclear transcription factors such as NF-AT and NF-kappaB or by direct interaction with Vitamin D responsive elements in the promoter regions of cytokine genes. Dendritic cells (DCs) are primary targets for the immunomodulatory activity of 1,25(OH)(2)D(3), as indicated by inhibited DC differentiation and maturation, leading to down-regulated expression of MHC-II, costimulatory molecules and IL-12. Moreover, 1,25(OH)(2)D(3) enhances IL-10 production and promotes DC apoptosis. Together, these effects of 1,25(OH)(2)D(3) inhibit DC-dependent T cell activation. Immunomodulation by 1,25(OH)(2)D(3) and its analogs in vivo has been demonstrated in different models of autoimmune diseases and transplantation. Moreover, combining analogs with other immunosuppressants leads to synergism in models of autoimmunity and transplantation. The availability of 1,25(OH)(2)D(3) analogs with immunomodulatory activity at non-hypercalcemic doses may allow exploitation of their immunomodulatory effects in a clinical setting of treatment of autoimmune diseases and prevention of allograft rejection.

[1]  C. Mathieu,et al.  1alpha,25-dihydroxyvitamin D3 induces an autoantigen-specific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543). , 2000, Diabetes.

[2]  A. Santoni,et al.  Vitamin D3: a transcriptional modulator of the interferon‐γ gene , 1998 .

[3]  C. Mathieu,et al.  Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3 , 1994, Diabetologia.

[4]  M. Uskoković,et al.  A 1α,25-Dihydroxyvitamin D3 Analog Enhances Regulatory T-Cells and Arrests Autoimmune Diabetes in NOD Mice , 2002 .

[5]  C. Mathieu,et al.  Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). , 2002, Diabetes.

[6]  Lars Klareskog,et al.  A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses collagen‐induced arthritis (CIA) without causing hypercalcaemia , 1998, Clinical and experimental immunology.

[7]  C. Mathieu,et al.  Treatment of autoimmune diabetes recurrence in non‐obese diabetic mice by mouse interferon‐β in combination with an analogue of 1α,25‐dihydroxyvitamin‐D3 , 2002 .

[8]  A. Licata.  Bisphosphonate therapy : Management of osteoporosis, 1997 , 1997 .

[9]  R. Bouillon,et al.  1,25-Dihydroxyvitamin D3 Prevents Insulitis in NOD Mice , 1992, Diabetes.

[10]  L. Frati,et al.  Negative Regulation of CD95 Ligand Gene Expression by Vitamin D3 in T Lymphocytes1 , 2002, The Journal of Immunology.

[11]  H. DeLuca,et al.  Vitamin D and autoimmune diabetes , 2003, Journal of cellular biochemistry.

[12]  H. DeLuca,et al.  1,25-Dihydroxyvitamin D3 prolongs graft survival without compromising host resistance to infection or bone mineral density. , 1998, Transplantation.

[13]  E. Marcinkowska.  A Run for a Membrane Vitamin D Receptor , 2001, Neurosignals.

[14]  R. Koren,et al.  1,25‐Dihydroxyvitamin D3 enhances prostaglandin E2 production by monocytes , 1986, FEBS letters.

[15]  J. Park,et al.  Nuclear factor of activated T cells (NFAT) as a molecular target for 1alpha,25-dihydroxyvitamin D3-mediated effects. , 1998, Journal of immunology.

[16]  H. DeLuca,et al.  Current understanding of the molecular actions of vitamin D. , 1998, Physiological reviews.

[17]  C. Mathieu,et al.  Analogs of 1,25-dihydroxyvitamin D3 as dose-reducing agents for classical immunosuppressants. , 2000, Transplantation.

[18]  David F. Richards,et al.  In Vitro Generation of Interleukin 10–producing Regulatory CD4+ T Cells Is Induced by Immunosuppressive Drugs and Inhibited by T Helper Type 1 (Th1)– and Th2-inducing Cytokines , 2002, The Journal of experimental medicine.

[19]  C. Mathieu,et al.  1alpha,25-dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis. , 2004, Journal of autoimmunity.

[20]  L. Adorini,et al.  1α,25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation , 2000, The Journal of Immunology.

[21]  Chilakamarti V. Ramana,et al.  Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription , 2002, Molecular and Cellular Biology.

[22]  Huub F. J. Savelkoul,et al.  1α,25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells1 , 2001, The Journal of Immunology.

[23]  J. Peters,et al.  1,25‐Dihydroxyvitamin D3 Exerts Opposing Effects to IL‐4 on MHC Class‐II Antigen Expression, Accessory Activity, and Phagocytosis of Human Monocytes , 1993, Scandinavian journal of immunology.

[24]  C. Mathieu,et al.  Seasonality of birth in patients with type 1 diabetes , 2002, The Lancet.

[25]  L. Adorini,et al.  Regulatory T Cells Induced by 1α,25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance1 , 2001, The Journal of Immunology.

[26]  H. DeLuca,et al.  Prolongation of allograft survival by 1,25-dihydroxyvitamin D3. , 1998, Transplantation.

[27]  R. Bouillon,et al.  Partial prevention of active Heymann nephritis by lα, 25 dihydroxyvitamin D3 , 1993, Clinical and experimental immunology.

[28]  C. Mathieu,et al.  Prevention of autoimmune destruction of syngeneic islet grafts in spontaneously diabetic nonobese diabetic mice by a combination of a vitamin D3 analog and cyclosporine. , 1998, Transplantation.

[29]  A. Mantovani,et al.  Impairment of cytokine production in mice fed a vitamin D3-deficient diet. , 2013, Immunology.

[30]  V. Panichi,et al.  1,25-dihydroxyvitamin D(3) dose-dependently inhibits LPS-induced cytokines production in PBMC modulating intracellular calcium. , 2001, Transplantation proceedings.

[31]  L. Freedman,et al.  1,25-Dihydroxyvitamin D3 Inhibits IFN-γ and IL-4 Levels During In Vitro Polarization of Primary Murine CD4+ T Cells1 , 2002, The Journal of Immunology.

[32]  R. Bouillon,et al.  Prevention of murine experimental allergic encephalomyelitis: cooperative effects of cyclosporine and 1 α, 25-(OH)2D3 , 1995, Journal of Neuroimmunology.

[33]  Elina Hyppönen,et al.  Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study , 2001, The Lancet.

[34]  S. Harris.  Can vitamin D supplementation in infancy prevent type 1 diabetes? , 2002, Nutrition reviews.

[35]  C. Tzanno-Martins,et al.  Immunomodulatory effects of vitamin D analog KH1060 on an experimental skin transplantation model. , 1999, Transplantation proceedings.

[36]  Imad Hakim,et al.  Modulation of TNF‐α expression in bone marrow macrophages: Involvement of vitamin D response element , 2003, Journal of cellular biochemistry.

[37]  L. Mazzucchelli,et al.  1α,25‐Dihydroxycholecalciferol reduces rejection and improves survival in rat liver allografts , 2001 .

[38]  T. Y. Chan,et al.  Vitamin D Deficiency and Susceptibility to Tuberculosis , 2000, Calcified Tissue International.

[39]  C. Mathieu,et al.  Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice , 2004, Diabetologia.

[40]  L. Mazzucchelli,et al.  1alpha,25-dihydroxyvitamin D3 shows strong and additive immunomodulatory effects with cyclosporine A in rat renal allotransplants. , 2002, Kidney international.

[41]  C. Johnsson,et al.  MC 1288 — A vitamin D analogue with immunosuppressive effects on heart and small bowel grafts , 1994, Transplant international : official journal of the European Society for Organ Transplantation.

[42]  J M Lemire,et al.  1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. , 1991, The Journal of clinical investigation.

[43]  R. Bouillon,et al.  1,25‐Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide‐induced apoptosis in non‐obese diabetic (NOD) mice and protects against diabetes , 1998, Clinical and experimental immunology.

[44]  M. Cantorna,et al.  1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. , 2000, The Journal of nutrition.

[45]  H. DeLuca,et al.  Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. , 1995, Biochimica et biophysica acta.

[46]  Aristides G. Eliopoulos,et al.  Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells1 , 2003, The Journal of Immunology.

[47]  C. Carlberg,et al.  Gene regulation by vitamin D3. , 1998, Critical reviews in eukaryotic gene expression.

[48]  C. Mathieu,et al.  Prevention of type I diabetes in nonobese diabetic mice by late intervention with nonhypercalcemic analogs of 1,25-dihydroxyvitamin D3 in combination with a short induction course of cyclosporin A. , 1998, Endocrinology.

[49]  C. Mathieu,et al.  Synergism between sirolimus and 1,25-dihydroxyvitamin D3 in vitro and in vivo , 1997, Journal of Neuroimmunology.

[50]  H. DeLuca,et al.  Vitamin D deficiency suppresses cell-mediated immunity in vivo. , 1993, Archives of biochemistry and biophysics.

[51]  C. Mathieu,et al.  Identification and immune regulation of 25‐hydroxyvitamin D‐1‐α‐hydroxylase in murine macrophages , 2000, Clinical and experimental immunology.

[52]  C. Mathieu,et al.  Prevention of type I diabetes in NOD mice by nonhypercalcemic doses of a new structural analog of 1,25-dihydroxyvitamin D3, KH1060. , 1995, Endocrinology.

[53]  L. Freedman,et al.  A Two-Hit Mechanism for Vitamin D3-Mediated Transcriptional Repression of the Granulocyte-Macrophage Colony-Stimulating Factor Gene: Vitamin D Receptor Competes for DNA Binding with NFAT1 and Stabilizes c-Jun , 1999, Molecular and Cellular Biology.

[54]  A. Tobler,et al.  Granulocyte-macrophage colony-stimulating factor. Sensitive and receptor-mediated regulation by 1,25-dihydroxyvitamin D3 in normal human peripheral blood lymphocytes. , 1987, The Journal of clinical investigation.

[55]  C. Mathieu,et al.  Analogs of 1α,25‐dihydroxyvitamin D3 as pluripotent immunomodulators , 2003 .

[56]  C. Mathieu,et al.  Potential role of 1,25(OH)2 vitamin D3 as a dose-reducing agent for cyclosporine and FK 506. , 1994, Transplantation proceedings.

[57]  C. Mathieu,et al.  Combination of a 1,25-dihydroxyvitamin D3 analog and a bisphosphonate prevents experimental autoimmune encephalomyelitis and preserves bone. , 2003, Bone.

[58]  J. Lemire,et al.  1,25-Dihydroxyvitamin D3 Attenuates of Expression of Experimental Murine Lupus of MRL/1 Mice , 1992 .

[59]  M. Haussler,et al.  The Nuclear Vitamin D Receptor: Biological and Molecular Regulatory Properties Revealed , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[60]  C. Mathieu,et al.  1,25-dihydroxycholecalciferol: endocrinology meets the immune system , 2002, Proceedings of the Nutrition Society.

[61]  M. Cippitelli,et al.  Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. , 1998, The Journal of clinical investigation.

[62]  S. Samila,et al.  A vitamin D analog, MC1288, inhibits adventitial inflammation and suppresses intimal lesions in rat aortic allografts. , 1997, Transplantation.

[63]  C. Mathieu,et al.  The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. , 2002, Trends in molecular medicine.