Resistance to infections with Heligmosomoides bakeri is associated with a significant quantitative trait locus (QTL–Hbnr1) on mouse chromosome 1 (MMU1). We exploited recombinant mice, with a segment of MMU1 from susceptible C57Bl/10 mice introgressed onto MMU1 in intermediate responder NOD mice (strains 1094 and 6109). BALB/c (intermediate responder) and C57Bl/6 mice (poor responder) were included as control strains and strain 1098 (B10 alleles on MMU3) as NOD controls. BALB/c mice resisted infection rapidly and C57Bl/6 accumulated heavy worm burdens. Fecal egg counts dropped by weeks 10–11 in strain 1098, but strains 1094 and 6109 continued to produce eggs, harbouring more worms when autopsied (day 77). PubMed search identified 3 genes (Ctla4, Cd28, Icos) as associated with ‘Heligmosomoides’ in the B10 insert. Single nucleotide polymorphism (SNP) differences in Ctla4 could be responsible for regulatory changes in gene function, and a SNP within a splice site in Cd28 could have an impact on function, but no polymorphisms with predicted effects on function were found in Icos. Therefore, one or more genes encoded in the B10 insert into NOD mice contribute to the response phenotype, narrowing down the search for genes underlying the H. bakeri resistance QTL, and suggest Cd28 and Ctla4 as candidate genes.

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.

Experiments in rodent models of insulin-dependent diabetes mellitus (IDDM) suggest that destruction of pancreatic p cells can be both initiated and inhibited by certain environmental factors such as dietary constituents. We studied nutritional impact of certain protein sources of natural-ingredient, non-purified (NP) rodent diet on diabetes incidence and insulitis severity in the spontaneous diabetic, non-obese diabetic (NOD) mouse. Long-term ad lib. feeding of diets containing wheat flour (800 g/kg), and to a lesser extent soya-bean meal (400 g/kg), were associated with relatively high diabetes incidence (65 and 45% respectively), whereas a diet based on hydrolysed casein (HC; 200 g/kg) as the only source of protein significantly (compared with the wheat-flour diet) inhibited expression of diabetes (22 YO). Feeding a hypo-allergenic soya-bean-protein hydrolysate resulted in diabetes incidence and insulitis severity similar to that of the soya-bean-meal-fed group. This may indicate that protein hydrolysis per se may not be necessary for dietary modification of diabetes in the NOD mouse. The window of vulnerability to diabetogenic diets was found to be between weaning and about 70 d of age. In the diabetic mice insulitis was less frequent in the HC-fed group when compared with those fed NP (P = 0.04), soya- bean meal (P = 0.03), soya-bean-protein hydrolysate (P = 0.012) or wheat flour (P = 0.0002). In the non-diabetic mice the wheat-flour diet was associated with a high insulitis severity in comparison with the HC group (P = 0.004). Early avoidance of NP diet was associated with lower degree of insulitis in both diabetic (P = 0.00003) and non-diabetic mice (P =0.001) when compared with the mice fed on the HC diet later in life. These findings are contributing to further clarification of diabetes-promoting dietary constituents, which may have some nutritional implications for IDDM-susceptible children.