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1,25-dihydroxycholecalciferol: endocrinology meets the immune system

Published online by Cambridge University Press:  28 July 2008

Evelyne van Etten ,
Brigitte Decallonne  and
Chantal Mathieu
Evelyne van Etten
Affiliation:
Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium
Brigitte Decallonne
Affiliation:
Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium
Chantal Mathieu*
Affiliation:
Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium
*
*Corresponding author: C. Mathieu, fax + 32 16 345934, email [email protected]
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Abstract

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Previous work has demonstrated that, besides its effects on Ca and bone metabolism, the active form of cholecalciferol, 1,25-dihydroxycholecalciferol (1,25(OH)2D3), possesses pronounced immunomodulatory effects. In non-obese diabetic (NOD) mice primary (before disease onset), secondary (after insulitis but before diabetes onset) as well as tertiary (after transplantation of syngeneic islets) prevention of diabetes was demonstrated with 1,25(OH)2D3 and its chemically-manufactured non-hypercalcaemic analogues. 1,25(OH)2D3 exerts its immune effects both at the level of the T lymphocyte (shift in cytokine profile from T-helper (Th)1 to Th2, enhanced sensitivity to apoptosis-inducing signals) as well as at the level of the antigen-presenting cell (reduced antigen presentation, reduced production of Th1-promoting cytokines, reduced expression of co-stimulatory molecules). Also, physiologically, 1,25(OH)2D3 is believed to have a role in the immune system by serving as a negative feedback signal, limiting the mounted immune reaction. To test the clinical applicability of 1,25(OH)2D3 as treatment for type 1 diabetes in genetically-at-risk young children, we tested whether short-term early-life intervention with cholecalciferol or non-hypercalcaemic analogues of 1,25(OH)2D3 could prevent diabetes in NOD mice. Significant protection of pancreatic β cells against autoimmune destruction was observed in analogue-treated and especially in cholecalciferol-treated NOD mice as compared with controls (P < 0.005). This short-term early-life intervention was, however, not able to protect the mice from developing diabetes during their lifetime. Possible solutions are longer or combined treatments with other immunomodulators that have synergistic effects with 1,25(OH)2D3 and its analogues.

Keywords

1,25-DihydroxycholecalciferolType 1 diabetesNOD mice
Type
Joint National Nurses Nutritional Group and Parenteral and Enteral Group of the British Dietetic Association Symposium on ‘Working in Partnership’
Information
Proceedings of the Nutrition Society , Volume 61 , Issue 3 , August 2002 , pp. 375 - 380
Copyright
Copyright © The Nutrition Society 2002

References

Bouillon, R, Verstuyf, AM, Verlinden, L, Branisteanu, D, Mathieu, C & Van Baelen, H (1995) Non-hypercalcemic pharmacological aspects of vitamin D analogs. Biochemical Pharmacology 50, 577–583.CrossRefGoogle ScholarPubMed
Branisteanu, D, Mathieu, C & Bouillon, R (1997) Synergism between sirolimus and 1,25-dihydroxyvitamin D3 in vitro and in vivo. Journal of Neuroimmunology 79, 138–147.CrossRefGoogle ScholarPubMed
Casteels, K, Bouillon, R, Waer, M & Mathieu, C (1995) Immunomodulatory effects of 1,25(OH)2D3. Current Opinion in Nephrology and Hypertension 4, 313–318.CrossRefGoogle Scholar
Casteels, K, Bouillon, R, Waer, M, Valckx, D, Overbergh, L, Laureys, J & Mathieu, C (1998) Prevention of type I diabetes by late intervention with non-hypercalcemic analogues of vitamin D3 in combination with cyclosporin A. Endocrinology 139, 95–102.CrossRefGoogle Scholar
Casteels, K, Waer, M, Bouillon, R, Depovere, J, Valckx, D, Laureys, J & Mathieu, C (1998) 1,25-Dihydroxyvitamin D3 restores sensitivity to cyclophosphamide-induced apoptosis in NOD mice and protects against diabetes. Clinical and Experimental Immunology 112, 181–187.CrossRefGoogle ScholarPubMed
Casteels, K, Waer, M, Laureys, J, Depovere, J, Gysemans, C, Bouillon, R & Mathieu, C (1998) Sex difference in resistance to dexamethasone-induced apoptosis in NOD mice: treatment with 1,25(OH)2D3 restores defect. Diabetes 47, 1033–1037.CrossRefGoogle ScholarPubMed
Casteels, K, Waer, M, Laureys, J, Valckx, D, Depovere, J, Bouillon, R & Mathieu, C (1998) Prevention of autoimmune destruction of syngeneic islet grafts in spontaneously diabetic NOD mice by a combination of a vitamin D3 analogue and cyclosporin A. Transplantation 65, 1–8.CrossRefGoogle Scholar
Chomarat, P, Banchereau, J, Davoust, J & Packula, AK (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nature Immunology 1, 510–514.CrossRefGoogle ScholarPubMed
Dahlquist, GG, Patterson, C & Soltesz, G (1999) Vitamin D supplement in early childhood and risk for type 1 (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 42, 51–54.Google Scholar
Gysemans, C, Van Etten, E, Overbergh, L, Verstuyf, A, Waer, M, Bouillon, R & Mathieu, C (2002) Treatment of autoimmune diabetes recurrence in non-obese diabetic mice by mouse interferon-b in combination with an analogue of 1a,25-dihydroxyvitamin-D3. Clinical and Experimental Immunology 128, 213–220.CrossRefGoogle Scholar
Gysemans, C, Waer, M, Bouillon, R & Mathieu, C (2001) A combination of KH1060, a vitamin D3 analogue and cyclosporin prevents early graft failure and prolongs graft survival of xenogeneic islets in non obese diabetic mice. Transplantation Proceedings 33, 2365.Google Scholar
Gysemans, C, Waer, M, Bouillon, R & Mathieu, C (2001) Leflunomide and its analogue X920715 synergize with cyclosporin A in preventing early graft failure and delaying graft rejection of xenogeneic islets in non-obese-diabetic mice. Transplantation Proceedings 33, 2094–2095.CrossRefGoogle Scholar
Gysemans, CA, Waer, M, Valckx, D, Laureys, J, Mikhalsky, D, Bouillon, R & Mathieu, C (2000) Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-b mRNA in the grafts. Diabetes 49, 1992–1997.CrossRefGoogle Scholar
Hahn, HJ, Kuttler, B, Mathieu, C & Bouillon, R (1997) 1,25-dihydroxyvitamin D3 reduces MHC antigen expression on pancreatic beta-cells in vitro. Transplantation Proceedings 29, 2156–2157.CrossRefGoogle ScholarPubMed
Kimpimaki, T, Erkkola, M, Korhonen, S, Kupila, A, Virtanen, SM, Ilonen, J, Simell, O & Knip, M (2001) Short-term exclusive breast-feeding predisposes young children with increased genetic risk of Type 1 diabetes to progressive beta-cell autoimmunity. Diabetologia 44, 63–69.Google ScholarPubMed
Mathieu, C (2000) Current limitations of islet transplantation. Transplantation Proceedings 33, 1707–1708.CrossRefGoogle Scholar
Mathieu, C & Adorini, L (2002) The coming of age of 1,25-dihydroxyvitamin D3 analogs as immunomodulatory agents. Trends in Molecular Medicine 8, 174–179.CrossRefGoogle ScholarPubMed
Mathieu, C, Bouillon, R, Rutgeerts, O, Vandeputte, M & Waer, M(1994)a The activated form of vitamin D [1,25(OH)2D3\ and its analogues as dose reducing agents for cyclosporin and FK506 in vitro and in vivo. Transplantation Proceedings 26, 3048–3049.Google Scholar
Mathieu, C, Casteels, K, Waer, M, Laureys, J, Valckx, D & Bouillon, R (1997) Prevention of diabetes recurrence after islet transplantation in NOD mice by analogues of 1,25(OH)2D3 in combination with CyA. Transplantation Proceedings 28, 3095.Google Scholar
Mathieu, C, Laureys, J, Sobis, H, Vandeputte, M, Waer, M & Bouillon, R (1992) 1,25-Dihydroxyvitamin D3 prevents insulitis in NOD mice. Diabetes 41, 1491–1495.CrossRefGoogle ScholarPubMed
Mathieu, C, Waer, M, Casteels, K, Laureys, J & Bouillon, R (1995) Prevention of type 1 diabetes in NOD mice by non-hypercalcemic doses of a new structural analogue of 1,25(OH)2D3, KH1060. Endocrinology 136, 866–872.CrossRefGoogle Scholar
Mathieu, C, Waer, M, Laureys, J, Rutgeerts, O & Bouillon, R (1994) Prevention of type I diabetes in NOD mice by 1,25-dihydroxyvitamin D3. Diabetologia 37, 552–558.CrossRefGoogle ScholarPubMed
Overbergh, L, Decallonne, B, Valckx, D, Verstuyf, A, Depovere, J, Laureys, L, Rutgeerts, O, Saint-Arnaud, R, Bouillon, R & Mathieu, C (2000) Identification and immune regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase in murine macrophages. Clinical and Experimental Immunology 120, 139–146.CrossRefGoogle ScholarPubMed
Overbergh, L, Decallonne, B, Waer, M, Rutgeerts, O, Valckx, D, Casteels, K, Laureys, J, Bouillon, R & Mathieu, C (2000) 1,25-Dihydroxyvitamin D3 induces an autoantigen specific Th1/Th2 immune shift in nonobese diabetic mice immunized with GAD65 (p524–543). Diabetes 49, 1301–1307.CrossRefGoogle ScholarPubMed
Penna, G & Adorini, L (2000) 1a,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation and survival of dendritic cells leading to impaired alloreactive T cell activation. Journal of Immunology 164, 2405–2411.CrossRefGoogle Scholar
Riachy, R, Vandewalle, B, Belaich, S, Kerr-Conte, J, Gmyr, V, Zerimech, F, D'Herbomez, M, Lefebvre, J & Patou, F (2001) Beneficial effect of 1,25-dihydroxyvitamin D3 on cytokine-treated human pancreatic islets. Journal of Endocrinology 169, 161–169.CrossRefGoogle ScholarPubMed
Van Etten, E, Branisteanu, D, Verstuyf, A, Waer, M, Bouillon, R & Mathieu, C (2000) Analogs of 1,25-dihydroxyvitamin D3 as dosereducing agents for classical immunosuppressants. Transplantation 69, 1932–1942.CrossRefGoogle ScholarPubMed
Van Halteren, AG, Van Etten, E, De Jongh, EC, Bouillon, R, Roep, BO & Mathieu, C (2002) Redirection of human autoreactive T cells upon interaction with dendritic cells modulated by TX527, an analogue of 1,25-dihydroxyvitamin D3. Diabetes (In the Press).CrossRefGoogle Scholar
Veldman, CM, Cantorna, MT & Deluca, HF (2000) Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Archives of Biochemistry and Biophysics 374, 334–338.CrossRefGoogle ScholarPubMed
Verstuyf, A, Segaert, S, Verlinden, L, Bouillon, R & Mathieu, C (2000) Recent developments in the use of vitamin D analogues. Expert Opinion on Investigational Drugs 9, 443–455.CrossRefGoogle ScholarPubMed