Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153470 (Spleen)
 4,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Freshly isolated, mature dendritic cells (DC) from mouse lymphoid organs were analyzed by immunofluorescent labeling and flow cytometry to determine the number of discrete subpopulations and to assess possible lineage markers. The permanence of surface markers was then determined by overnight culture of the DC. Three DC subtypes were discerned, CD8alpha- DEC-205-, CD8alpha+ DEC-205+, and CD8alpha- DEC-205+, with different tissue distributions. The majority of DC expressed high levels of class II MHC, expressed CD11c, and expressed the costimulator molecules CD80, CD86, and CD40; CD80 and CD40 were further up-regulated on culture. DC also expressed low levels of L-selectin that were up-regulated on culture. Thymus contained predominantly CD8alpha+ DEC205+ CD11b- DC, resembling a major subpopulation of DC in other tissues but unique in expressing BP-1. Spleen contained predominantly two DC populations in equal proportions: one CD8alpha+ DEC-205+ CD11b- as in the thymus, and the other CD8alpha- DEC-205- CD11b+. Lymph nodes contained the same two DC populations as in spleen, but in addition a third population of CD8alpha- DEC-205+ CD11b- DC. The CD8alpha expression of splenic DC subpopulations did not change on culture. Although DEC-205 was up-regulated on culture so all DC became positive, the difference in the level between subpopulations was maintained. However, CD11b was up-regulated on culture, so all subpopulations became positive and finally expressed equivalent levels. Some aspects of this complex, but discrete, pattern of surface marker expression can be correlated with differences in lineage origin and functional activity of the DC.
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PMID:Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. 921 70

Dendritic cells (DC) are the professional antigen-presenting cells of the immune system. Previous studies have demonstrated that targeting foreign antigens to DC leads to enhanced antigen (Ag)-specific responses in vivo. However, the utility of this strategy for the generation of MAbs has not been investigated. To address this question we immunized mice with IgG-peptide conjugates prepared with the hamster anti-murine CD11c MAb N418. Synthetic peptides corresponding to two different exposed regions of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), a human C-type lectin, were conjugated to N418 using thiol-based chemistry. The N418 MAb served as the targeting molecule and synthetic peptides as the Ag (MAb-Ag). A rapid and peptide specific serum IgG response was produced by Day 7 when the synthetic peptides were linked to the N418 MAb, compared to peptide co-delivered with the N418 without linkage. Spleen cells from N418-peptide immunized mice were fused on Day 10, and three IgG1/k monoclonal antibodies (MAbs) were selected to one of the peptide epitopes (MID-peptide). One of the MAbs, Novik 2, bound to two forms of recombinant DC-SIGN protein in enzyme-linked immunosorbent assay (ELISA), and was specifically inhibited by the MID-peptide in solution. Two of these MAbs show specific binding to DC-SIGN expressed by cultured human primary DC. We conclude that in vivo DC targeting enhances the immunogenicity of synthetic peptides and is an effective method for the rapid generation of MAbs to predetermined epitopes.
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PMID:Rapid monoclonal antibody generation via dendritic cell targeting in vivo. 1271 87

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine models, but the antitumor effects on established tumors have been minimal. Conversely, the major role of the heat shock protein gp96, localized in the endoplasmic reticulum (ER), is to act as a molecular chaperone to assist the folding of nascent polypeptide chains in the ER. gp96 derived from tumor cells elicits specific protective immunity against parental tumors, presumably through the transport of tumor-specific peptides to antigen-presenting cells and the maturation of dendritic cells (DCs). However, the therapeutic effects of tumor-derived gp96 on established tumors have not been promising. The present study analyzes the therapeutic effects of GM-CSF gene-transduced Lewis lung cancer (LLC/GM) cells combined with LLC-derived gp96 on established wild-type LLC tumors in immunocompetent C57BL/6 mice. Therapy with either irradiated LLC/GM cells or LLC-derived gp96 barely affected established LLC tumor growth. The antitumor effect was significantly enhanced when 1 microg of LLC-derived gp96 was administered together with 1 x 10(6) irradiated LLC/GM cells (p < 0.05). The antitumor effects of irradiated LLC/GM cells and LLC-derived gp96 required mainly CD8(+) T cells. Spleen cells obtained from mice vaccinated with irradiated LLC/GM cells and LLC-derived gp96 showed specific CD8 cytotoxic activities against LLC cells (specific lysis rate of approximately 28%). This antibody response was not associated with a synergic effect of the combination therapy. Moreover, draining lymph nodes from mice immunized with irradiated LLC/GM cells and LLC-derived gp96 contained more migrating mature CD11c(+) cells (higher levels of CD86 and major histocompatibility complex [MHC] class II molecules) compared with those from any other immunization protocols. These results suggest that the combination of irradiated LLC/GM cells and tumor-derived gp96 has potential as a new immunogene therapeutic strategy against lung cancer.
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PMID:Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice. 1280 36

We have identified in the rat a new subset of MHC class II(+) CD4(+)CD3(-)CD11b(-) leukocytes that produce high amounts of type I IFN upon viral stimulation and that appeared homologous to plasmacytoid DC (pDC) previously described in humans and mice. These cells exhibited the following phenotype: CD5(+),CD90(+),CD45R(+),CD45RC(+),CD11c(-),CD161a(+),CD200(+),CD172a(+),CD32(+),CD86(+). Rat pDC did not express the DC-specific marker OX62 and were more abundant in the spleen than the classical CD4(+) and CD4(-) subsets of OX62(+)CD11b(+) DC we previously described that produced very little, if any, type I IFN. Spleen pDC exhibited an undifferentiated morphology and rapidly died in vitro, but showed extensive dendrite formation, survival, maturation, and moderate type I IFN production upon stimulation by oligonucleotides containing type B CpG motifs (CpG ODN). Type A CpG ODN and CD40 ligand induced pDC to produce large amounts of type I IFN, but did not promote maturation. CpG ODN and CD40 ligand, but not influenza virus, induced IL-12p40 and IL-6 secretion. Spleen pDC did not produce IL-12p70, TNF-alpha, IL-1beta, or IL-10 using these stimulation conditions. Correlating with their strong responsiveness to virus and CpG ODN, rat pDC specifically expressed Toll-like receptor 7 and 9 mRNA. Fresh spleen pDC were poor stimulators of allogenic CD4(+) and CD8(+) T cells, but became potent inducers of allogenic T cell proliferation as well as Th1 differentiation after stimulation by type B CpG. Therefore, rat pDC appear very similar to human pDC, indicating that the specific phenotype and functions of pDC have been highly conserved between species.
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PMID:Rat plasmacytoid dendritic cells are an abundant subset of MHC class II+ CD4+CD11b-OX62- and type I IFN-producing cells that exhibit selective expression of Toll-like receptors 7 and 9 and strong responsiveness to CpG. 1518 27

The presence of circulating villous lymphocytes (VLs) in lymphoma patients usually points to splenic marginal zone B-cell lymphoma (SMZL), even if the VLs can be found occasionally in other small B-cell lymphomas. However, those cells are variably described, and detailed cytologic characterization is often lacking. We identified lymphoma cases with numerous basophilic VLs among the large group of splenic lymphoma with VLs, and for further delineation, 37 cases with this particular cytology were analyzed. Patients, predominantly older men, presented with moderate lymphocytosis and splenomegaly without pancytopenia. The monoclonal B cells expressed IgM + D, IgM + G, IgM or IgG, as well as CD76 and CD11c, frequently CD103, and rarely CD123. Spleen sections were peculiar, with atrophic white pulp and a monomorphic diffuse lymphoma infiltration in a congested red pulp. Bone marrow infiltration was interstitial and intrasinusoidal without extensive fibrosis. Cytogenetic analysis showed a frequent absence of clonal aberrations (68%). Most cases (79%) were IgH mutated, with an overrepresentation of V(H)3 and V(H)4 gene families. These results, as well as the clinical evolution, show that those lymphoma cases represent a homogeneous group distinct from SMZL and reminiscent of hairy cell leukemia variant, perhaps corresponding to a separate lymphoma entity.
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PMID:Splenic red pulp lymphoma with numerous basophilic villous lymphocytes: a distinct clinicopathologic and molecular entity? 1804 95

Spleen stromal cells are critical determinants of dendritic cell (DC) development in spleen. The spleen stromal line, namely STX3, supports DC differentiation in vitro from overlaid bone marrow cells while the lymph node stromal line, namely 2RL22, does not. Here we have characterised the hematopoietic support capacity of each stroma, and analysed lineage origin of the stromal cell lines by gene profiling using microarrays. Stromal co-culture experiments were performed using bone marrow cells as a source of hematopoietic progenitors. A characteristic immature myeloid-like CD11c(+)CD11b(+)CD86(+)MHC-II(/lo)B220()CD8alpha() DC is produced after 14 days in STX3 cocultures, while 2RL22 cocultures produce only monocyte/macrophage-like cells. No other hematopoietic cell type is produced. The STX3 and 2RL22 stroma were compared by transcriptome analysis utilising Affymetrix Murine U74Av2 genechips to identify gene expression related to differential hematopoietic support function. Data mining was used to determine cell surface marker expression reflecting endothelial cells and fibroblasts, as well as adhesion molecules contributing to the microenvironment. STX3 shows gene expression reflective of early endothelial cells, while 2RL22 expresses markers specific to fibroblasts. The expression of genes like Flt1, CD34, Mcam, and Eng distinguishes STX3 as an early immature endothelial cell lacking markers of angioblasts or hemangioblasts like Tal1/SCL, Tie1, Tie2, Kdr or Prom1/AC133. The absence of expression of genes like Vwf and Cd31 distinguishes STX3 from fully differentiated vascular endothelial cells. In contrast, the 2RL22 lymph node stroma specifically expresses genes related to fibroblastic-like cells like osteoblasts with expression of Vdr (Vitamin D receptor), and epithelial cells with expression of Krt13 (keratins). Gene expression data identifies STX3 as splenic endothelial cells, independently able to support the outgrowth of immature, myeloid DC-like cells from progenitors present in bone marrow, while 2RL22 lymph node fibroblastic cells provide support for development of monocytes/macrophages.
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PMID:Gene signature of stromal cells which support dendritic cell development. 1856 35

Multiple genetic factors contribute to the clinical variability of spontaneous systemic lupus erythematosus (SLE) but their role in drug-induced SLE remain largely unknown. Hydrocarbon oil-induced SLE depends on mesothelial cell apoptosis and Toll-like receptor (TLR)-7-mediated induction of type I interferons. Hence, we hypothesized that TIR8/SIGIRR, an endogenous TLR inhibitor, prevents oil-induced SLE. Sigirr-deficient dendritic cells expressed higher TLR7 mRNA levels and TLR7 activation resulted in increased IL-12 production in vitro. In vivo, lack of SIGIRR increased surface CD40 expression on spleen CD11c(+) dendritic cells and MX-1, TNF, IL-12, BAFF and BCL-2 mRNA expression 6 months after pristane injection. Spleen cell counts of CD4(-)/CD8(-) 'autoreactive' T cells and B220(+) B cells were also increased in Sigirr(-/-) mice. Serum autoantibody analysis revealed that Sigirr deficiency specifically enhanced the production of rheumatoid factor (from 4 months of age) and anti-snRNP IgG (from 5 months of age), while anti-Smith IgG or anti-dsDNA IgG were independent of the Sigirr genotype. This effect was sufficient to significantly aggravate lupus nephritis in Sigirr-deficient mice. Structure model prediction identified the BB loop of SIGIRR's intracellular TIR domain to interact with TLR7 and MyD88. BB loop deletion was sufficient to completely abrogate SIGIRR's inhibitory effect on TLR7 signalling. Thus, TIR8/SIGIRR protects from hydrocarbon oil-induced lupus by suppressing the TLR7-mediated activation of dendritic cells, via its intracellular BB loop.
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PMID:Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis. 2011 71

Spleen is known to contain multiple dendritic and myeloid cell subsets, distinguishable on the basis of phenotype, function and anatomical location. As a result of recent intensive flow cytometric analyses, splenic dendritic cell (DC) subsets are now better characterized than other myeloid subsets. In order to identify and fully characterize a novel splenic subset termed "L-DC" in relation to other myeloid cells, it was necessary to investigate myeloid subsets in more detail. In terms of cell surface phenotype, L-DC were initially characterized as a CD11b(hi)CD11c(lo)MHCII(-)Ly6C(-)Ly6G(-) subset in murine spleen. Their expression of CD43, lack of MHCII, and a low level of CD11c was shown to best differentiate L-DC by phenotype from conventional DC subsets. A complete analysis of all subsets in spleen led to the classification of CD11b(hi)CD11c(lo)MHCII(-)Ly6C(lo)Ly6G(-) cells as monocytes expressing CX3CR1, CD43 and CD115. Siglec-F expression was used to identify a specific eosinophil population, distinguishable from both Ly6C(lo) and Ly6C(hi) monocytes, and other DC subsets. L-DC were characterized as a clear subset of CD11b(hi)CD11c(lo)MHCII(-)Ly6C(-)Ly6G(-) cells, which are CD43(+), Siglec-F(-) and CD115(-). Changes in the prevalence of L-DC compared to other subsets in spleens of mutant mice confirmed the phenotypic distinction between L-DC, cDC and monocyte subsets. L-DC development in vivo was shown to occur independently of the BATF3 transcription factor that regulates cDC development, and also independently of the FLT3L and GM-CSF growth factors which drive cDC and monocyte development, so distinguishing L-DC from these commonly defined cell types.
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PMID:Redefining Myeloid Cell Subsets in Murine Spleen. 2679 92

Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.
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PMID:Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. 2716 85