Summary
1,25 dihydroxyvitamin D3, the active form of vitamin D, has immunomodulatory properties in vitro and in vivo. We report that treatment with 1,25 dihydroxyvitamin D3 (5 μg/kg on alternate days) prevents the development of clinical diabetes in NOD mice, an animal model of human autoimmune diabetes. Diabetes incidence in female NOD mice at the age of 200 days was reduced to 8% in the 1,25 dihydroxyvitamin D treated group vs 56% in the control group (p<0.0001). In parallel, treatment with 1,25 dihydroxyvitamin D3 resulted in a complete normalisation of the capacity to induce suppressor mechanisms in an autologous MLR, which is severely depressed in control NOD mice. The existence of such suppressor cells was confirmed in transfer experiments, whereby cotransfer of splenocytes from 1,25 dihydroxyvitamin D3 treated NOD mice prevented diabetes transfer by splenocytes from diabetic NOD mice into irradiated, 6–8-week-old male NOD mice. Other known immune defects of the NOD mice, such as defective natural killer cell killing of YAC-1 targets and defective thymocyte activation by anti-CD3 were not corrected. The pharmacological doses of 1,25 dihydroxyvitamin D3 were universally well tolerated as reflected by a normal weight gain of the mice. Serum calcium was increased (2.5±0.2 vs 2.2±0.2 mmol/l in the control group, P<0.005), whereas osteocalcin levels nearly doubled and bone calcium content was halved. These findings show that 1,25 dihydroxyvitamin D3 can prevent diabetes in NOD mice, probably through the correction of their defective suppressor function.
Article PDF
Similar content being viewed by others
Abbreviations
- 1,25(OH)2D3 :
-
1,25 dihydroxyvitamin D3
- NOD:
-
non-obese-diabetic
- MLR:
-
mixed lymphocyte reaction
- 60Co:
-
cobalt
- 51Cr:
-
sodium chromate
- SI:
-
stimulation index
- NK:
-
natural killer
References
Makino S, Kunimoto K, Muraoka Y et al. (1980) Breeding of a non-obese diabetic strain of mice. Exp Anim 29: 1–13
Castano L, Eisenbarth G (1990) Type I diabetes. A chronic autoimmune disease of humans, mouse and rat. Annu Rev Immunol 8: 647–679
Lampeter F, Signore A, Gale E, Pozzilli P (1989) Lessons from the NOD mouse for the pathogenesis and immunotherapy of human type I (insulin-dependent) diabetes mellitus. Diabetologia. 32: 703–708
Rossini AA, Greiner DL, Friedman HP, Mordes JP (1993) Immunopathogenesis of diabetes mellitus. Diabetes Rev 1(1): 43–75
Hewison M (1992) Vitamin D and the immune system. J Endocrinol 132: 173–175
Rigby WFC (1988) The immunobiology of vitamin D. Immunol Today 9: 54–58
Provvedini DM, Manolagas SC, Deftos LJ (1983) 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221: 1181–1183
Provvedini DM, Manolagas SC (1989) 1,25 dihydroxyvitamin D3 receptor distribution and effects in subpopulations of normal human T lymphocytes. J Clin Endocrinol Metab 68: 774–779
Bhalla A, Amento E, Serog B, Glimcher L (1984) 1,25-Dihydroxy-vitamin D3 inhibits antigen-induced T cells activation. J Immunol 133: 1748–1755
Rigby WFC, Denome S, Fanger NW (1987) Regulation of lymphokine production and human T lymphocyte activation by 1,25 dihydroxy-vitamin D3. J Clin Invest 79: 1659–1664
Rigby WFC, Yirinec B, Oldershaw RL, Fanger MW (1987) Comparison of the effects of 1,25 dihydroxyvitamin D3 on T lymphocyte subpopulations. Eur J Immunol 17: 563–566
Reichel H, Koeffler HP, Tobler A, Norman AW (1987) 1α, 25-Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 84: 3385–3391
Saggese G, Federico G, Balestri M, Torriolo A (1989) Calcitriol inhibits the PHA-induced production of IL-2 and IFN-gamma and the proliferation of human peripheral blood leukocytes while enhancing the surface expression of HLA class II molecules. J Endocrinol Invest 12: 329–335
Meehan MA, Kerman RH, Lemire JM (1992) 1,25-Dihydroxyvitamin D3 enhances the generation of non specific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 140: 400–409
Lemire JM (1992) Immunomodulatory role of 1,25-dihydroxyvitamin D3. J Cell Biochem 49: 26–31
Rigby WFC, Waugh MG (1992) Decreased accessory cell function and costimulatory activity by 1,25-dihydroxyvitamin D3-treated monocytes. Arthritis Rheum 35: 110–119
Fournier C, Gepner P, Sadouk M, Charriere J (1990) In vivo beneficial effects of cyclosporin A and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis. Clin Immunol Immunopathol 54: 53–63
Lemire J, Archer C (1991) 1,25-Dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest 87: 1103–1107
Mathieu C, Laureys J, Sobis H, Vandeputte M, Waer M, Bouillon R (1992) 1,25-Dihydroxyvitamin D3 prevents insulitis in NOD mice. Diabetes 41(11): 1491–1495
Verhaeghe J, Bouillon R, Lissens W, Visser WJ, Van Assche FA (1988) Diabetes and low Ca-P diet have opposite effects on adult and fetal bone mineral metabolism. Am J Physiol 254: E496-E504
Serreze DV, Leiter EH (1988) Defective activation of T suppressor cell function in nonobese diabetic mice. J Immunol 140(11): 3801–3807
Kataoka S, Satoh J, Fujiya H et al. (1983) Immunological aspects of the nonobese diabetic (NOD) mouse. Abnormalities of cellular immunity. Diabetes 32: 247–253
Zipris D, Lazarus AH, Crow AR, Hadzija M, Delovitch TL (1991) Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice. J Immunol 146: 3763–3771
Harrada M, Makino S (1986) Suppression of overt diabetes in NOD mice by anti-thymocyte serum or anti-Thy 1.2 antibody. Exp Anim 35: 501–504
Koike T, Itoh Y, Ishii T et al. (1987) Preventive effect of monoclonal anti-L3T4 antibody on the development of diabetes in NOD mice. Diabetes 36: 539–541
Mori Y, Suko M, Okudaira H et al. (1986) Preventive effects of cyclosporine on diabetes in NOD mice. Diabetologia 29: 244–247
Miyagawa J, Yamamoto K, Hanafusa T et al. (1990) Preventive effect of a new immunosuppressant FK-506 on insulitis and diabetes in non-obese diabetic mice. Diabetologia 33: 503–505
Serreze DV, Hamaguchi K, Leiter EH (1989) Immunostimulation circumvents diabetes in NOD/Lt mice. J Autoimmunity 2: 759–776
Manolagas SC, Hustmeyer FG, Yu XP (1990) Immunomodulating properties of 1,25-dihydroxyvitamin D3. Kidney Int 38 [Suppl 29]: S9-S16
Walters MR (1992) Newly identified actions of the vitamin D endocrine system. Endocrine Res 13: 719–764
Bikle DD (1992) Clinical counterpart: vitamin D: new actions, new analogs, new therapeutic potential. Endocrine Res 13: 765–784
Hess AD, Donnenberg AD, Tutschka PJ, Santos G (1983) Effects of cyclosporin A on human lymphocyte response in vitro. J Immunol 130(2): 717–721
Zarrabeitia MT, Riancho JA, Amado JA, Olmos JM, Gonzalez-Macias J (1992) Effect of calcitriol on the secretion of prostaglandin E2, IL-1 and tumor necrosis factor alpha by human monocytes. Bone 13(2): 185–189
Hutchings PR, Cooke A (1990) The transfer of autoimmune diabetes in NOD mice can be inhibited or accelerated by distinct cell populations present in normal splenocytes taken from young males. J Autoimmunity 3: 175–185
Boitard C, Yasunami R, Dardenne M, Bach JF (1989) T cell mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med 169: 1669–1680
Binderup L, Bramm E (1988) Effects of a novel vitamin D analogue MC903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 37: 889–895
Bouillon R, Allewaert K, Xiang DZ, Tan BK, Van Baelen H (1991) Vitamin D analogs with low affinity for the vitamin D binding protein: enhanced in vitro and decreased in vivo activity. J Bone Mineral Res 6: 1051–1057
Binderup L, Latini S, Kissmeyer AM (1991) New vitamin D3 analogues with potent effects on cell growth regulation and immune responses: structure-activity studies. In: A. W. Norman, R. Bouillon, M. Thomasset (eds) Vitamin D. Gene regulation, structure-function analysis and clinical application. De Gruyter, Berlin, pp. 478–485
Latini S, Binderup L (1991) KH1060. A new vitamin D analogue with potent effects on cell-mediated immune responses in vitro. In: A. W. Norman, R. Bouillon, M. Thomasset (eds) Vitamin D. Gene regulation, structure-function analyses and clinical application. De Gruyter, Berlin, pp. 516–519
Abe J, Nakamura K, Takita Y, Nakano T, Irie H, Nishii Y (1990) Prevention of immunological disorders in MRL/I mice by a new synthetic analogue of vitamin D3: 22oxa-1α,25-Dihydroxyvitamin D3. J Nutr Sci Vitaminol 36: 21–31
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mathieu, C., Waer, M., Laureys, J. et al. Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3 . Diabetologia 37, 552–558 (1994). https://doi.org/10.1007/BF00403372
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00403372