1,25-dihydroxycholecalciferol: endocrinology meets the immune system.
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 beta 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.
van Etten
Evelyne
E
Laboratory of Experimental Medicine and Endocrinology, Catholic University of Leuven, Herestraat 49, Belgium.
Decallonne
Brigitte
B
Mathieu
Chantal
C
D000818:Animals; D002117:Calcitriol / Q000276:immunology* / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004703:Endocrine System / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007107:Immune System / Q000276:immunology / Q000502:physiology*; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD
D002117:Calcitriol