Human CD56(bright) NK cells accumulate in the maternal decidua during pregnancy and are found in direct contact with fetal trophoblasts. Several mechanisms have been proposed to explain the inability of NK cells to kill the semiallogeneic fetal cells. However, the actual functions of decidual NK (dNK) cells during pregnancy are mostly unknown. Here we show that dNK cells, but not peripheral blood-derived NK subsets, regulate trophoblast invasion both in vitro and in vivo by production of the interleukin-8 and interferon-inducible protein-10 chemokines. Furthermore, dNK cells are potent secretors of an array of angiogenic factors and induce vascular growth in the decidua. Notably, such functions are regulated by specific interactions between dNK-activating and dNK-inhibitory receptors and their ligands, uniquely expressed at the fetal-maternal interface. The overall results support a 'peaceful' model for reproductive immunology, in which elements of innate immunity have been incorporated in a constructive manner to support reproductive tissue development.

Adult neovascularization relies on the recruitment of circulating cells, but their angiogenic roles and recruitment mechanisms are unclear. We show that the endothelial growth factor VEGF is sufficient for organ homing of circulating mononuclear myeloid cells and is required for their perivascular positioning and retention. Recruited bone marrow-derived circulating cells (RBCCs) summoned by VEGF serve a function distinct from endothelial progenitor cells. Retention of RBCCs in close proximity to angiogenic vessels is mediated by SDF1, a chemokine induced by VEGF in activated perivascular myofibroblasts. RBCCs enhance in situ proliferation of endothelial cells via secreting proangiogenic activities distinct from locally induced activities. Precluding RBCCs strongly attenuated the proangiogenic response to VEGF and addition of purified RBCCs enhanced angiogenesis in excision wounds. Together, the data suggest a model for VEGF-programmed adult neovascularization highlighting the essential paracrine role of recruited myeloid cells and a role for SDF1 in their perivascular retention.

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Prion protein (PrP)Sc , the only known component of the prion, is present mostly in the brains of animals and humans affected with prion diseases. We now show that a protease-resistant PrP isoform can also be detected in the urine of hamsters, cattle, and humans suffering from transmissible spongiform encephalopathies. Most important, this PrP isoform (UPrP Sc ) was also found in the urine of hamsters inoculated with prions long before the appearance of clinical signs. Interestingly, intracerebrally inoculation of hamsters with UPrP Sc did not cause clinical signs of prion disease even after 270 days, suggesting it differs in its pathogenic properties from brain PrP Sc . We propose that the detection of UPrP Sc can be used to diagnose humans and animals incubating prion diseases, as well as to increase our understanding on the metabolism of PrP Sc in vivo.

The scrapie isoform of the prion protein, PrP Sc , is the only identified component of the infectious prion, an agent causing neurodegenerative diseases such as Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. Following proteolysis, PrP Sc is trimmed to a fragment designated PrP 27-30. Both PrP Sc and PrP 27-30 molecules tend to aggregate and precipitate as amyloid rods when membranes from prion-infected brain are extracted with detergents. Although prion rods were also shown to contain lipids and sugar polymers, no physiological role has yet been attributed to these molecules. In this work, we show that prion infectivity can be reconstituted by combining Me 2 SO-solubilized PrP 27-30, which at best contained low prion infectivity, with nonprotein components of prion rods (heavy fraction after deproteination, originating from a scrapie-infected hamster brain), which did not present any infectivity. Whereas heparanase digestion of the heavy fraction after deproteination (originating from a scrapie-infected hamster brain), before its combination with solubilized PrP 27-30, considerably reduced the reconstitution of infectivity, preliminary results suggest that infectivity can be greatly increased by combining nonaggregated protease-resistant PrP with heparan sulfate, a known component of amyloid plaques in the brain. We submit that whereas PrP 27-30 is probably the obligatory template for the conversion of PrP C to PrP Sc , sulfated sugar polymers may play an important role in the pathogenesis of prion diseases.PrP Sc , the abnormal isoform of PrP C , is the only known component of the prion, an agent causing fatal neurodegenerative disorders such as bovine spongiform encephalopathy and CreutzfeldtJakob disease (1). It has been postulated that prion diseases propagate by the conversion of PrP C molecules into proteaseresistant and insoluble PrP Sc molecules by a mechanism in which PrP Sc serves as a template (2). Whereas some PrP Sc may be insoluble in vivo (3), it is well documented that most PrP Sc , as well as its protease-resistant core denominated PrP 27-30, precipitate into insoluble aggregates (also known as prion rods) when membranes from scrapie-infected brains are extracted with detergents such as sarkosyl (4). In addition to PrP Sc , prion aggregates were shown to contain nonprotein components, which include sphingolipids as well as polysaccharides (5-7). The traces of nucleic acids present in prion rods are believed to be too small to function as coding tools (8).No physiological role has ever been attributed to any nonprotein components of prion rods.Disruption of prion rods into detergent protein lipid complexes resulted in the retention of their protease resistance property concomitantly with an increase in their prion infectivity, suggesting that solubilized PrP Sc is more infectious than the aggregated prion protein (9). Contrarily, disruption of prion rods by sonication and SDS resulted in a protease-sensitive PrP with complete loss of infectivity (10).As opposed to methods to disr...