Previous studies have reported that LPS injections prevent diabetes

establishment Dabrafenib in vitro in NOD mice. In the original report, i.v. administration of LPS was initiated at 6 weeks of age, and repeated every week [35]. In a recent work, 3- to 4-week-old mice were treated weekly with 5 μg LPS i.p. [39]. Together these studies indicated that LPS treatment initiated before extensive infiltration of the pancreatic islets is protective. Our data extend these previous results by showing that LPS treatment is also highly effective in preventing progression from late insulitis (12 weeks) to diabetes. Intriguingly, administration of LPS to BDC2.5 TCR transgenic NOD animals precipitated diabetes [54]. In contrast to normal NOD, the vast majority of T cells in the BDC2.5 animals are specific for an islet antigen presented by the MHC class II molecule Ag7. It is likely that in this system the pro-inflammatory effect of LPS prevailed over its tolerogenic action owing to the over-representation of autoreactive cells. Other protective treatments in NOD mice have been shown to elicit distinct and even disparate outcomes, according to the number of engaged diabetogenic cells (e.g. [55]). We showed that LPS administration must be sustained to ensure long-lasting protection of NOD mice. Similar requirement was reported for another bacterial compound,

OM85 [56]. In contrast, a single injection of CFA, an emulsion containing mycobacterium ADAM7 extract, affords life-long protection [32, 33]. As CFA can neither be resolved nor eliminated by the body, it is likely that the selleck compound release of the bacterial compound is actually long lasting. The general principle associated with the ‘hygiene hypothesis’ is that certain infections early in life promote the development of a healthy immune system endowed with robust self-tolerance mechanisms. Yet, the prototypic example of experimental protection of NOD mice by environmental factors

is actually provided by exposure of a NOD colony to either uncontrolled or SPF environment [29, 30]. It would be interesting to test whether, as suggested by human epidemiology studies [29, 30], NOD mice raised in an infectious microorganism-rich environment until young adult age, and only then decontaminated and maintained in an SPF environment would remain protected. LPS tolerogenic effects in vivo are known for long, notably in mismatched graft and in delayed type hypersensitivity [46, 47]; however, the mechanism of action remains elusive. Here, we demonstrate that LPS protects NOD mice from diabetes occurrence through the enhancement of Treg activities. By performing adoptive transfer experiments we formally established that the protection afforded by LPS is mediated by a subset of cells encompassed within the CD25+ subset of lymphocytes.