Monocytes and cells of the dendritic cell lineage circulate in blood and eventually migrate into tissue where they further mature and serve various functions, most notably in immune defense. Over ...recent years these cells have been characterized in detail with the use of cell surface markers and flow cytometry, and subpopulations have been described. The present document proposes a nomenclature for these cells and defines 3 types of monocytes (classical, intermediate, and nonclassical monocytes) and 3 types of dendritic cells (plasmacytoid and 2 types of myeloid dendritic cells) in human and in mouse blood. This classification has been approved by the Nomenclature Committee of the International Union of Immunological Societies, and we are convinced that it will facilitate communication among experts and in the wider scientific community.
Prion diseases are neurodegenerative conditions that cause extensive damage to nerve cells within the brain and can be fatal. Some prion disease agents accumulate first in lymphoid tissues, as they ...make their journey from the site of infection, such as the gut, to the brain. Studies in mouse models have shown that this accumulation is obligatory for the efficient delivery of prions to the brain. Indeed, if the accumulation of prions in lymphoid tissues is blocked, disease susceptibility is reduced. Therefore, the identification of the cells and molecules that are involved in the delivery of prions to the brain might identify targets for therapeutic intervention. This review describes the current understanding of the mechanisms involved in the delivery of prions to the brain.
Dendritic cells (DCs) in the intestine are heterogeneous. Phenotypically different populations of conventional DCs have been identified in the intestinal lamina propria, Peyer's patches, and in the ...draining mesenteric lymph nodes, to which these DCs constitutively migrate. Markers used to identify these populations include major histocompatibility complex class II, CD11c, CD8α, CD11b, and CD103. Extensive studies in rats, summarized here, which involved collection of migrating DCs by thoracic duct cannulation after mesenteric lymphadenectomy, have clearly demonstrated that the subsets of migrating intestinal lymph DCs have different functional properties. The subsets might play different roles in the induction of oral tolerance and in driving systemic immune responses after vaccination or intestinal stimulation with Toll-like receptor ligands. The use of these surgical techniques allows investigation of the functions of purified subsets of migrating DCs. However, in the rat, these studies are limited by the range of available reagents and are difficult to compare with data from other species in this fast-moving field. Recent refinements have enabled the collection of migrating intestinal DCs from mice; our initial results are described here. We believe that these studies will generate exciting data and have the potential to resolve important questions about the functions of migrating intestinal DC subsets.
We show that following oral inoculation, prions bind to ileal Peyer patch and cecal patch microfold cells (M cells) in vivo. Furthermore, we show evidence that the cecum acts a biological sump ...holding large concentrations of prions for relatively long periods, thus increasing the exposure time of cecal patch M cells. Our results show a critical initial step in the translocation of prions from the intestinal lumen of mammals in vivo, which is a precursor to infection.
Thalidomide Franks, Michael E; Macpherson, Gordon R; Figg, William D
The Lancet (British edition),
05/2004, Letnik:
363, Številka:
9423
Journal Article
Recenzirano
Odprti dostop
Despite its history as a human teratogen, thalidomide is emerging as a treatment for cancer and inflammatory diseases. Although the evolution of its clinical application could not have been predicted ...from the tragedy associated with its misuse in the past, its history serves as a lesson in drug development that underscores the need to understand the molecular pharmacology of a compound's activity, including associated toxicities. Here, we summarise the applications for thalidomide with an emphasis on clinical trials published over the past 10 years, and consider our knowledge of the molecular pharmacology of the drug in the context of clinical trial data, attempting to provide a mechanism-guided understanding of its activity.
To generate vaccines that protect mucosal surfaces, a better understanding of the cells required in vivo for activation of the adaptive immune response following mucosal immunization is required. ...CD11c(high) conventional dendritic cells (cDCs) have been shown to be necessary for activation of naive CD8(+) T cells in vivo, but the role of cDCs in CD4(+) T cell activation is still unclear, especially at mucosal surfaces. The activation of naive Ag-specific CD4(+) T cells and the generation of Abs following mucosal administration of Ag with or without the potent mucosal adjuvant cholera toxin were therefore analyzed in mice depleted of CD11c(high) cDCs. Our results show that cDCs are absolutely required for activation of CD4(+) T cells after oral and nasal immunization. Ag-specific IgG titers in serum, as well as Ag-specific intestinal IgA, were completely abrogated after feeding mice OVA and cholera toxin. However, giving a very high dose of Ag, 30-fold more than required to detect T cell proliferation, to cDC-ablated mice resulted in proliferation of Ag-specific CD4(+) T cells. This proliferation was not inhibited by additional depletion of plasmacytoid DCs or in cDC-depleted mice whose B cells were MHC-II deficient. This study therefore demonstrates that cDCs are required for successful mucosal immunization, unless a very high dose of Ag is administered.
Purpose
To explore the cultural context of Indigenous family entrepreneurs and to apply to them the concept of n-Culturals, thus contributing to validating the concept.
Design/methodology/approach
...Interview data collected from Wayuu entrepreneurs in La Guajira region of Colombia and from Māori entrepreneurs in the Rotorua region of New Zealand were analyzed qualitatively. The analysis primarily focused on Wayuu entrepreneurs, with the results for Māori entrepreneurs used for comparison, to help to interpret the Wayuu data.
Findings
For Wayuu entrepreneurs, family members play a range of crucial roles in enterprise operations, with the family and the kin-centered local Indigenous community emerging as an informal organization surrounding the enterprise. Family is the source of Indigenous culture, while the mainstream culture is centered on global Western business culture, rather than the culture of the country. The Indigenous entrepreneurs integrate the values of the two cultures in managing their enterprises, thus acting as n-Cultural. Māori entrepreneurs who managed enterprises with a strong Indigenous character were similar in this respect to Wayuu entrepreneurs.
Social implications
As n-Culturals integrating the values of Indigenous culture and the mainstream culture, Indigenous entrepreneurs develop valuable traits, becoming a valuable component of the human capital in their regions, even when their enterprises fail.
Originality/value
Existing research on multicultural individuals is largely limited to immigrants and expatriates. By characterizing Indigenous family entrepreneurs as n-Culturals, the present study contributes to validating the concept and opens the way for further research on how Indigenous entrepreneurs manage their multicultural identities.
Dendritic cells (DC) present peripheral Ags to T cells in lymph nodes, but also influence their differentiation (tolerance/immunity, Th1/Th2). To investigate how peripheral conditions affect DC ...properties and might subsequently regulate T cell differentiation, we examined the effects of a potent DC-activating, TLR-4-mediated stimulus, LPS, on rat intestinal and hepatic DC in vivo. Steady-state rat intestinal and hepatic lymph DC are alpha(E2) integrin(high) (CD103) and include two subsets, signal regulatory protein alpha (SIRPalpha)(hi/low), probably representing murine CD8alphaalpha(-/+) DC. Steady-state lamina propria DC are immature; surface MHC class II(low), but steady-state lymph DC are semimature, MHC class II(high), but CD80/86(low). Intravenous LPS induced rapid lamina propria DC emigration and increased lymph DC traffic without altering SIRPalpha(high)/SIRPalpha(low) proportions. CD80/86 expression on lymph or mesenteric node DC was not up-regulated after i.v. LPS. In contrast, i.v. LPS stimulated marked CD80/86 up-regulation on splenic DC. CD80/86 expression on intestinal lymph DC, however, was increased after in vitro culture with TNF-alpha or GM-CSF, but not with up to 5 mug/ml LPS. Steady-state SIRPalpha(low) DC localized to T cell areas of mesenteric nodes, spleen, and Peyer's patch, whereas SIRPalpha(high) DC were excluded from these areas. Intravenous LPS stimulated rapid and abundant SIRPalpha(high) DC accumulation in T cell areas of mesenteric nodes and spleen. In striking contrast, i.v. LPS had no effect on DC numbers or distribution in Peyer's patches. Our results suggest that any explanation of switching between tolerance and immunity as well as involving changes in DC activation status must also take into account differential migration of DC subsets.
Abstract
To generate vaccines that protect mucosal surfaces, a better understanding of the cells required in vivo for activation of the adaptive immune response following mucosal immunization is ...required. CD11chigh conventional dendritic cells (cDCs) have been shown to be necessary for activation of naive CD8+ T cells in vivo, but the role of cDCs in CD4+ T cell activation is still unclear, especially at mucosal surfaces. The activation of naive Ag-specific CD4+ T cells and the generation of Abs following mucosal administration of Ag with or without the potent mucosal adjuvant cholera toxin were therefore analyzed in mice depleted of CD11chigh cDCs. Our results show that cDCs are absolutely required for activation of CD4+ T cells after oral and nasal immunization. Ag-specific IgG titers in serum, as well as Ag-specific intestinal IgA, were completely abrogated after feeding mice OVA and cholera toxin. However, giving a very high dose of Ag, 30-fold more than required to detect T cell proliferation, to cDC-ablated mice resulted in proliferation of Ag-specific CD4+ T cells. This proliferation was not inhibited by additional depletion of plasmacytoid DCs or in cDC-depleted mice whose B cells were MHC-II deficient. This study therefore demonstrates that cDCs are required for successful mucosal immunization, unless a very high dose of Ag is administered.
The intestinal innate immune system continually interacts with commensal bacteria, thus oral vaccines should induce extra/alternative activation of DC, potentially through TLR. To examine this we ...collected intestinal lymph DC (iL‐DC) under steady‐state conditions and after feeding resiquimod (R‐848), a synthetic TLR7/8 ligand, which we showed induces complete emptying of gut DC into lymph. iL‐DC are heterogeneous with subset‐specific functions. In this study we determined the kinetics of iL‐DC subset release, activation and cytokine secretion induced by R‐848. We show that L‐DC comprise three distinct subsets (CD172ahigh, CD172aint and CD172alow) present with similar frequencies in intestinal but not hepatic lymph. No iL‐DC express TLR7 mRNA, and only CD172a+ iL‐DC express TLR8. However, after oral R‐848 administration, output of all three subsets increases dramatically. CD172ahigh DC release precedes that of CD172alow DC, and the increased frequency of CD25high iL‐DC is restricted to the two CD172a+ subsets. After feeding R‐848 only CD172ahigh iL‐DC secrete IL‐6 and IL‐12p40. However, CD172aint and CD172ahigh DC secrete similar but markedly lower amounts when stimulated in vitro. These results highlight the importance of in vivo approaches to assess adjuvant effects on DC and give novel insights into the subset‐specific effects of an oral TLR ligand on intestinal DC.
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