In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice.
Immune cells carry receptors for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; vitamin D receptor (VDR)] and individuals with severe vitamin D deficiency have immune abnormalities. The aim of this study was to investigate the role of vitamin D in the immune system by studying VDR-knockout (VDR-KO) mice. VDR-KO mice had the same metabolic phenotype as rachitic animals with severe hypocalcemia. Leukocytosis, lymphocyte subset composition in different immune organs, and splenocyte proliferation to several stimuli were normal, except for a lower response to anti-CD3 stimulation (simulation index [SI] of 13 +/- 4 vs. 24 +/- 9 in wild-type mice; p < 0.01). Macrophage chemotaxis was impaired (41 +/- 19% vs. 60 +/- 18% in wild-type mice; p < 0.01) but phagocytosis and killing were normal. In vivo rejection of allogeneic (31 +/- 12 days vs. 45 +/- 26 days of survival in wild-type mice, NS) or xenogeneic (10 +/- 2 days vs. 16 +/- 9 days of survival in wild-type mice, NS) islet grafts was comparable with wild-type mice. Surprisingly, VDR-KO mice were protected from low-dose streptozotocin-induced diabetes mellitus (LDSDM; 5% vs. 65% in wild-type mice; p < 0.001). Correcting hypocalcemia by use of lactose-rich or polyunsaturated fat-rich diets fully restored the immune abnormalities in vitro and the sensitivity to diabetes in vivo. On the other hand, treatment with 1,25(OH)2D3 protected wild-type mice against diabetes but did not protect normocalcemic VDR-KO mice. We conclude that immune defects observed in VDR-KO mice are an indirect consequence of VDR disruption because they can be restored by calcium homeostasis normalization. This study proves that although 1,25(OH)2D3 is a pharmacologic and probably a physiological immunomodulator, its immune function is redundant. Moreover, we confirm the essential role of calcium in the immune system.
Mathieu
C
C
Laboratory of Experimental Medicine and Endocrinology, LEGENDO, Catholic University of Leuven, Belgium.
Van Etten
E
E
Gysemans
C
C
Decallonne
B
B
Kato
S
S
Laureys
J
J
Depovere
J
J
Valckx
D
D
Verstuyf
A
A
Bouillon
R
R
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002112:Calcifediol / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006996:Hypocalcemia / Q000276:immunology / Q000378:metabolism; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002112:Calcifediol; D002118:Calcium