No abstract

Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM).

SUMMARYReceptors for 1,25(OH) 2 vitaminD 3 are found in most immune cells and important immunological effects have been described in vitro, reflected by its capacity to prevent autoimmunity and to prolong graft survival. The aim of this study was to examine the presence and nature of the enzyme responsible for final activation of the molecule, 1-a -hydroxylase, in murine macrophages and to analyse its regulation and possible role in the immune system. Peritoneal macrophages from C57Bl/6 mice were incubated with lipopolysaccharide (LPS; 100 m g/ml), interferon-gamma (IFN-g; 500 U/ml) or a combination of both. By quantitative reverse transcriptase-polymerase chain reaction, using primers based on the murine renal cDNA sequence, low levels of 1-a -hydroxylase mRNA were detected in freshly isolated cells (18^7 Â 10 26 copies/b -actin copies). Analysis of the cDNA sequence of the gene revealed identical coding sequences for the macrophage and renal enzymes. mRNA levels rose three-fold with LPS (NS), but a six-fold increase was seen after IFN-g stimulation (P , 0´05). Combining LPS and IFN-g did not result in a major additional increase, but addition of cyclosporin A further increased levels 2´5-fold both in IFN-g-and combination-stimulated cells (P , 0´05). Time course analysis revealed that upregulation of 1-a -hydroxylase was a late phenomenon, preceded by the up-regulation of activating macrophage products such as IL-1 and tumour necrosis factor-alpha. Finally, a defect in 1-ahydroxylase up-regulation by immune stimuli was found in autoimmune non-obese diabetic mice. In conclusion, we propose that the up-regulation of 1-a -hydroxylase in activated macrophages, resulting in the synthesis of 1,25(OH) 2 D 3 , might be a negative feedback loop in inflammation. A defect in this system might be an additional element in tipping the balance towards autoimmunity.

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant or -intolerant gastrointestinal stromal tumours (GIST). Several studies have identified unexpected rates of thyroid dysfunction with sunitinib treatment. We performed a prospective observational study with the aim of more accurately defining the incidence and severity of hypothyroidism in RCC or GIST patients receiving sunitinib. Thyroid function was assessed at baseline and on days 1 and 28 of each treatment cycle. Thyroid antibodies were assessed at baseline and during follow-up if abnormal thyroid function tests were recorded. Sixteen patients (27%) developed sub-or clinical hypothyroidism and required hormone replacement and 20 patients (34%) showed at least one elevated thyroid-stimulating hormone not requiring therapeutic intervention. Twenty patients (34%) did not develop any biochemical thyroid abnormality. Thus, sunitinib can induce (sub-) clinical hypothyroidism, warranting close monitoring of thyroid function. We propose a new algorithm for managing this side effect in clinical practise.

Aims/hypothesis. 1,25-dihydroxyvitamin D 3 , the active form of vitamin D, prevents Type 1 diabetes in non-obese diabetic (NOD) mice. Epidemiological data show a threefold increase in human Type 1 diabetes when vitamin D deficiency was present in the first months of life. To evaluate whether a similar dietary deficiency affects diabetes incidence in NOD mice, we generated NOD mice with vitamin D deficiency in early life. Methods. Breeding pairs of NOD mice, as well as their offspring (test mice), were kept in surroundings devoid of ultraviolet light and were fed a vitamin Ddepleted diet for 100 days. Mice were followed for 250 days. Results. At 250 days, 35% (12/35) male and 66% (22/33) female vitamin D-deficient mice were diabetic compared to 15% (6/40, p=0.05) and 45% (13/29, p<0.01) of the control mice. At 100 days no difference in insulitis was seen, but more vitamin D-deficient mice were glucose intolerant. Higher IL1 expression was detected in islets of vitamin D-deficient mice and their peritoneal macrophages had an aberrant cytokine profile (low IL1 and IL6, high IL15). Thymus and lymph nodes of vitamin D-deficient mice contained less CD4 + CD62L + cells. Conclusion/interpretation. Vitamin D status increases the expression of Type 1 diabetes in NOD mice. Our data in NOD mice, as well as human epidemiological data, point to the importance of preventing vitamin D deficiency in early childhood. Controlling this dietary factor could be an easy and safe way to reduce the incidence of Type 1 diabetes in subjects who are genetically at risk. [Diabetologia (2004)