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Results for “Integrin alphaXbeta2”

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PubMed1999

CD154 inhibits tumor-induced apoptosis in dendritic cells and tumor growth.

We have recently demonstrated that murine and human tumors induce apoptosis of dendritic cells (DC). Here, we evaluated the effect of CD40 ligation on the survival of tumor-associated DC and tumor growth. Retroviral transduction of MC38 colon carcinoma cells with the CD154 gene resulted in inhibition of tumor growth. This effect was abrogated in IL-12 knockout mice. Immunohistochemical analysis revealed an increase in CD11c+ (N418) and CD8+ but not NLDC-145+ cells in CD154-transfected tumors in wild-type mice. This increase was less pronounced in IL-12-deficient mice. In vitro, overexpression of CD154 on tumor cells significantly decreased the level of tumor-induced DC apoptosis. Surprisingly, the CD154-induced protection of DC from tumor-induced apoptosis was IL-12 independent in vitro, suggesting an IL-12-dependent and an IL-12-independent mechanism of CD154-induced anti-tumor immunity. Thus, our data suggest a new strategy to improve immunotherapy of cancer by protecting DC from tumor-induced apoptosis.

Animals↗

PubMed1999

Dendritic cells associated with plasmablast survival.

A subset of myeloid dendritic cells is described which is associated with the ability of splenic and lymph node plasmablasts to survive and differentiate into plasma cells. Plasmablast-associated dendritic cells (PDC) are CD11c(high), DEC-205(-) and unlike conventional dendritic cells do not associate with T cells. The following findings suggest a requirement for PDC if plasmablasts are to differentiate to plasma cells. First, when large numbers of B cells are recruited into antibody responses and plasmablasts outgrow the PDC stroma, only those associated with PDC survive and differentiate into plasma cells. Conversely, if the number of PDC is increased by ligating their CD40, more plasmablasts survive on the expanded PDC stroma and differentiate into plasma cells. Finally, in T cell-deficient mice, the plasma cells that develop atypically in the T zones in response to thymus-independent antigens are associated with ectopic PDC.

Animals↗

PubMed1992

Coagulation inhibition and activation in pancreatic cancer. Changes during progress of disease.

BACKGROUND: To elucidate the disturbed hemostatic balance in patients with pancreatic cancer, the levels of plasma coagulation inhibition and coagulation activation were determined. METHODS: Twenty-one patients with adenocarcinoma of the pancreas were followed from time of diagnosis until death, using plasma analyses of coagulation inhibitors and a molecular marker of coagulation activation (thrombin-antithrombin complex, TAT). RESULTS: TAT was increased significantly at the time of diagnosis of pancreatic cancer compared with age-adjusted healthy control subjects (mean, 6.2 +/- 4.6 micrograms/l [standard deviation] versus 2.0 +/- 0.7 micrograms/l). It increased with disease progression (mean in the terminal phase, 14.1 micrograms/l; P < 0.05). Plasma levels of tissue factor pathway inhibitor (TFPI) also were increased significantly at the time of diagnosis compared with the control group (mean, 176 +/- 80% versus 127 +/- 29%; P < 0.05). The TFPI decreased to normal levels (121 +/- 40%) after surgical removal of the pancreatic tumor (n = 4) or relief of the cholestasis using a bypass procedure (n = 6). The TFPI levels increased significantly as the malignant disease progressed (from 1-3 months postoperatively to the terminal phase of disease; mean, 114 +/- 52% versus 154 +/- 60%). There was a significant positive correlation between TFPI levels and bilirubin levels; the correlation coefficient at diagnosis was 0.70 (P < 0.001). The levels of the coagulation inhibitors antithrombin, heparin cofactor II, protein C, and free protein S decreased significantly with disease progression compared with the normal values found at diagnosis. CONCLUSIONS: The mechanism for TFPI increase in cancer is not known. It may be related to the preoperative cholestasis seen in this study, but the increased degree of coagulation activation also may contribute.

Adenocarcinoma↗

PubMed2000

Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer.

BACKGROUND: Dendritic cells (DCs) are potent initiators of immune responses, and the infiltration of DCs into tumors may confer an improved prognosis. Whether the injection of DCs directly into tumors can mediate biologic activity was examined. METHODS: Patients with metastatic dermal or subcutaneous tumors received granulocyte-macrophage-colony stimulating factor to increase the numbers of peripheral blood monocyte precursors. DCs were then generated from monocytes obtained by phlebotomy with granulocyte-macrophage-colony stimulating factor and interleukin-4 in autologous plasma. Tumors were injected at multiple sites with 30 million autologous DCs per tumor. RESULTS: Seven patients with melanoma and three patients with breast carcinoma were treated. Injections were well tolerated. Regression of the injected tumors, beginning as early as 4 days after injection, was observed in four patients with melanoma and in two patients with breast carcinoma. Biopsies of regressing lesions showed lymphocyte infiltration associated with DCs and necrosis. Neutrophils and macrophages were not evident. Lymphocytes expanded from the regressing tumors proliferated in response to heat shock proteins, HSP70 and gp96, derived from autologous tumor. The DCs injected produced interferon-alpha and expressed Fas ligand mRNA but did not exhibit cytolytic activity in vitro. Expression of the costimulatory molecule, B7-2 (CD86), decreased on DCs after intratumoral injection. CONCLUSIONS: This pilot study demonstrates that DCs derived in vitro can exist viably after intratumoral injection and can mediate biologic activity in situ. Tumor-derived heat shock proteins may be involved in the antitumor activity observed.

Adult↗

PubMed2000

A new apoptotic pathway for the complement factor B-derived fragment Bb.

Apoptosis is involved in both the cellular and humoral immune system destroying tumors. An apoptosis-inducing factor from HL-60 myeloid leukemia cells was obtained, purified, and sequenced. The protein found has been identified as a human complement factor B-derived fragment Bb, although it is known that factor B is able to induce apoptosis in several leukemia cell lines. Monoclonal antibodies against fragment Ba and Bb inhibited the apoptotic activity of factor B. When the purified fragment Bb was used for apoptosis induction, only the anti-Bb antibody inhibited Bb-induced apoptosis, and not the anti-Ba antibody. The apoptosis-inducing activity was found to be enhanced under conditions facilitating the formation of Bb. Blocking TNF/TNFR or FasL/Fas interactions did not interfere with the factor B-induced apoptosis. CD11c (iC3bR) acts as the main subunit of a heterodimer binding to fragment Bb in the apoptosis pathway, and the factor B-derived fragment Bb was found to possess the previously unknown function of inducing apoptosis in leukemic cells through a suicide mechanism of myeloid lineage cells during the differentiation stage.

Antibodies, Monoclonal↗

PubMed2000

The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor.

Peptides associated with the heat shock protein gp96 induce a specific T cell response against cells from which gp96 is isolated. Recently, we have shown that gp96 binds to a yet unknown receptor present on dendritic cells (DC) and that receptor-mediated uptake is required for cross-presentation of gp96-associated peptides by DC. We now describe that gp96 mediates maturation of DC as determined by up-regulation of MHC class II and CD86 molecules, secretion of the cytokines IL-12 and TNF-alpha and enhanced T cell stimulatory capacity. Heat-denatured gp96 is not able to induce DC maturation and cytokine secretion. Furthermore, we show that mature DC are no longer able to bind gp96 molecules. Hence, the gp96 receptor is down-regulated on mature DC, suggesting that this receptor behaves similar to other receptors involved in antigen uptake like the scavenger receptor CD36, the mannose receptor or the integrins alpha(v)beta(3) and alpha(v)beta(5). Together, our findings provide an additional explanation for the remarkable immunogenicity of gp96 as a cross-priming antigen carrier and direct activator of DC.

Animals↗

PubMed2000

c-Myc inhibits CD11a and CD11c leukocyte integrin promoters.

The c-Myc transcription factor is an important regulator of cell growth and differentiation, and its gene repression ability seems to play a key role in Myc-mediated cellular transformation. Since Myc overexpression has been associated with reduced expression of beta1 and beta2 integrins, we have investigated the role of c-Myc on CD11a and CD11c transcription. c-Myc inhibited CD11a and CD11c integrin promoter activity in co-transfection experiments, and similar repression was obtained in cells where c-Myc expression (KmycB) or activity (Rat-1 c-MycER) is inducible. The c-Myc repression on the CD11c promoter was independent of the USF-binding site (USF-150), other putative Myc-binding elements, or the integrity of the initiator (Inr)-like sequence present at the major transcriptional start site. Analysis of deletion and mutant promoter constructs revealed that, in the absence of additional upstream cisacting elements, an AP-1-binding site at -60 (AP1-60) is required for c-Myc repressor activity. The c-Myc repressor activity on both integrin promoters was abrogated by deletion of c-Myc residues 106-143, a domain involved in Inr-dependent transcriptional repression. These results demonstrate a direct effect of c-Myc on integrin gene transcription and suggest the existence of a c-Myc-dependent mechanism for coupling leukocyte integrin expression to the cell proliferative state.

Cell Line↗

PubMed2002

A subfraction of B220(+) cells in murine bone marrow and spleen does not belong to the B cell lineage but has dendritic cell characteristics.

Although CD45R/B220 is commonly used as a pan-B cell marker in the mouse, not all B220(+) cells belong to the B cell lineage. Here we report the characterization of a subpopulation of B220(+)CD19(-) cells in murine bone marrow, which failed to express markers that are present in early CD19(--) B cell precursors. Instead, these cells expressed low levels of MHC class II and CD11c, which are typically found on dendritic cells (DC). Moreover, these B220(+)CD19(-)CD11c(+) cells expressed Gr-1, indicating that they are related to the recently identified murine plasmacytoid DC or their progenitors. Therefore, we evaluated surface marker expression of the B220(+)CD19(-)CD11c(+) cells in lymphoid tissues of C57BL/6 mice, recombinase activating gene-1 deficient mice, lacking mature B and T lymphocytes, and mice with a targeted disruption of the Ig H chain mu membrane exon (mu MT), lacking mature B lymphocytes. When comparing bone marrow and spleen, we found that the surface profiles of B220(+)CD19(-)CD11c(+) cells were remarkably similar, indicating that they are in a comparable maturation or activation stage in the two lymphoid compartments. In addition, the almost complete absence of peripheral B220(+) B-lineage cells in mu MT mice allowed the anatomical localization of the B220(+)CD19(-)CD11c(+) cells to the red pulp and the T cell areas in the spleen. Taken together, our findings indicate that the mouse bone marrow contains a recirculating population of B220(+)CD19(-) CD11c(+) plasmacytoid DC, the development of which is largely independent of the presence of mature T and B cells.

Animals↗

PubMed2002

Increased circulating CD11b+CD11c+ dendritic cells (DC) in aged BWF1 mice which can be matured by TNF-alpha into BLC/CXCL13-producing DC.

Dendritic cells (DC) play a pivotal role in regulating immune responses. We previously reported aberrant high production of B lymphocyte chemoattractant (BLC/CXCL13) by DC in aged BWF1 mice, amurine model for systemic lupus erythematosus (SLE). We describe here that CD11b+CD11c+ cells were markedly increased in the peripheral blood (PBL-DC) in aged BWF1, but not in similarly aged NZB or NZW mice. Part of PBL-DC showed a typical dendritic morphology and expressed MHC class II molecules, and had a weak, but significant antigen-presenting ability in mixed lymphocytereaction. PBL-DC were chemoattracted to several chemokines in vitro including secondary lymphoid tissue chemokine (SLC), liver and activation-regulated chemokine (LARC), RANTES, macrophage inflammatory protein-1alpha, whereas splenic mature DC from aged BWF1 mice were preferentially chemoattracted towards SLC. BLC production was induced when PBL-DC were cultured in the presence of TNF-alpha for 3 days. BLC expression was also induced in bone marrow-derived DC when they were differentiated into mature DC in the presence of TNF-alpha and IL-1beta, while both IFN-alpha and IFN-gamma failed to induce BLC expression in bone marrow-derived DC. Since TNF-alpha expression is increased in aged BWF1 mice, DC recruitment in the circulation and maturation into BLC-producing DC by TNF-alpha may play a pivotal role in the development of systemic autoimmune diseases.

Aging↗

PubMed1989

Increased expression of p150,95 and CR3 leukocyte adhesion molecules by mononuclear phagocytes in rheumatoid synovial membranes. Comparison with osteoarthritic and normal synovial membranes.

The expression of leukocyte adhesion molecules CR3 (CD11b) and p150,95 (CD11c) in synovial tissue was evaluated immunohistochemically. Although a significant proportion of synoviocytes in normal and osteoarthritic synovial membranes expressed the leukocyte common antigen and CR3, very few expressed the p150,95 molecule. In contrast, p150,95 was more evident in rheumatoid synovial membranes. Expression of this molecule was strongest in synovial membranes with a prominent macrophage infiltrate and accumulation of mononuclear phagocytes at the joint surface; p150,95 was also present on interdigitating cells in lymphoid collections. The patterns of expression suggest that these leukocyte adhesion molecules may be important in the diapedesis of mononuclear phagocytes into and through inflamed synovial membranes, as well as in cellular interactions within rheumatoid synovial membranes.

Adolescent↗

PubMed1996

Cellular adhesion molecules in rat adjuvant arthritis.

OBJECTIVE: To examine adhesion molecule expression during the progression of inflammation in a rheumatoid arthritis model of adjuvant-induced arthritis (AIA) in rats. METHODS: Immunohistochemical analysis was used to determine the distribution of the following adhesion molecules: lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18), Mac-1 and p150/95 (CD11bc/CD18), intercellular adhesion molecule 1 (ICAM-1), and CD44 in tissue sections from the ankle joints of rats with AIA. Control animals and those with AIA were killed at intervals over a 54-day period after injection with mineral oil and Mycobacterium butyricum, respectively. RESULTS: CD44 and LFA-1 were expressed on lymphocytes, macrophages, and synovial (ST) lining cells. CD44 expression on macrophages was found to be increased compared with control animals by day 18, and was significantly increased by day 41. CD44 expression on lymphocytes significantly increased earlier, on days 11-18. Increased LFA-1 expression on macrophages occurred late, on day 41. LFA-1 expression on lymphocytes was significantly increased on days 25, 47, and 54. ST lining cells exhibited two distinct periods of increased expression, one early, on days 11-25 and one later, on days 41-54. CD11b/c was expressed on macrophages and ST lining cells, showing a significant increase on AIA rat ST lining cells compared with control animals on day 4. No differences in ICAM-1 expression on endothelial cells between rats with AIA and controls were found on any of the days examined. CONCLUSION: CD44 expression is up-regulated on macrophages and lymphocytes during the early development of AIA, while LFA-1 expression is up-regulated later in the development of AIA. The up-regulation of CD44 and LFA-1 at different times in the development of AIA suggests an important role for these adhesion molecules in establishing and sustaining an inflammatory response in the AIA joint.

Animals↗

PubMed1984

Mechanism of activation of the classical pathway of complement by monoclonal IgE (DES). Restricted regulation of C4b by C4b-binding protein.

A human monoclonal IgE from patient DES, IgE (DES), has been shown to activate the classical pathway of complement. The mechanism of this activation has been investigated and can be summarized as follows: (a) IgE (DES) is able to bind and activate C1 in a dose-dependent fashion. This activation increases with the size of the aggregates used, but the affinity of C1 for IgE (DES) is weaker than for IgG. (b) A classical pathway C3 convertase can be assembled on IgE (DES) using purified C1, C4 and C2. The formation decay of this convertase is similar to that formed on IgG with an half-life of 9 min at 37 degrees C. (c) The extrinsic regulation of the C3 convertase by C4bp is restricted on IgE (DES) as compared to IgG. This restriction is shown on both the formation and the decay of the convertase. The mechanism of activation of the classical pathway of complement by IgE (DES) thus present some similarities with the assembly of the C3 convertase by the alternative pathway.

Antibodies, Monoclonal↗

PubMed1985

Ultrastructure of human C4-binding protein: proposition for a new model.

The structure of human C4-binding protein (C4bp), a regulatory factor of the classical C3 convertase of complement, has been under investigation for several years, but remains poorly understood. For example, the number of subunits in the C4bp molecule has not been established. In this report, we use two different techniques (partial reduction and electron microscopy) to clarify the structure of the C4bp. Our results lead us to propose a structural model which is quite different to that suggested before, i.e. the C4bp molecule appears to be a decamer. In addition to the disulfide bonds which link each subunit to another, a second disulfide interaction leads to the association of the subunits in pairs. Each pair of subunits appears as a filament ending in a globular head at the N-terminal extremity. The pairs of subunits join to form a conical central domain (at the C-terminal extremity) linked by disulfide bonds. The proposed pentameric shape of the C4bp is consistent with the stoichiometry of the C4b-C4bp interactions. The proposed model indicates an overall structural homology between C4bp and other binding proteins.

Carrier Proteins↗

PubMed1986

A model system for the study of the assembly and regulation of human complement C3 convertase (classical pathway).

The formation of classical C3 convertase of complement and its regulation by C4b-binding protein (C4bp) were studied using two different approaches: (a) the analysis was first carried out in fluid phase; a soluble stabilized C3 proconvertase could be assembled from C4b (or C4b-like C4) and iodine-treated C2 in the presence of Ni2+ ions. Upon activation of this complex by C1s, a C3 convertase C4b(C4b-like C4)-C2a was generated which was able to cleave purified C3. C4bp dissociated both C3 proconvertase and C3 convertase, but its effect was more important on C3 convertase. (b) A model system of phospholipid vesicles has been developed to study the assembly of the C3 convertase on a membrane. Among different phospholipid mixtures tested, P-glycerol/P-choline vesicles were found most effective for C4b binding. Optimal conditions were determined for C4b fixation on these vesicles; bound C4b participated in the formation of a functional membrane-associated C3 convertase. C4bp was found to bind to phospholipid vesicles with a higher affinity than C4b; it was able to dissociate the vesicle-associated C3 convertase.

Buffers↗

PubMed1988

Co-expression of Mac-1 and p150,95 on CD5+ B cells. Structural and functional characterization in a human chronic lymphocytic leukemia.

The leukocyte adhesion receptors (LAR) Mac-1 and p150,95 were thought to occur only on myeloid cells, but recently, mouse Ly-1+ (CD5+) B and pro-B cells were shown to bind M1/70 monoclonal antibody, an anti-Mac-1 antibody. Using immunoprecipitation, sodium dodecyl sulfate gel electrophoresis, immunofluorescence and flow cytometry, we have studied the expression of LAR in human CD5+ B cells from chronic lymphocytic leukemia (B-CLL) patients. 170,95 kDa Mac-1 and p150,95, as well as 180,95 kDa LFA-1 heterodimers are shown to be co-expressed on CD5+ mu + kappa + B cells from a patient where they retain their known function in homotypic cell-cell adhesion. Therefore, functional Mac-1 and p150,95 LAR are not restricted to myeloid cells.

Antibodies, Monoclonal↗

PubMed1995

Heterogenous glycosylation of ICAM-3 and lack of interaction with Mac-1 and p150,95.

Intercellular adhesion molecule (ICAM)-1, ICAM-2, and ICAM-3 have been identified as counter-receptors for the leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1). The other leukocyte integrins, Mac-1 and p150,95, also interact with ICAM-1. ICAM-1 and ICAM-3 are highly homologous, and an undefined ligand for Mac-1 is present on neutrophils where ICAM-3 is well expressed. In addition, glycosylation has been shown to affect the interaction of ICAM-1 with Mac-1. We therefore sought to characterize ICAM-3 heterogeneity and determine whether ICAM-3 was a ligand for either Mac-1 or p150,95. Despite extensive differences in N-linked glycosylation, ICAM-3 purified from lymphoid cells and from neutrophils supports adhesion of LFA-1-bearing cells equally well; however, neither supports adhesion of Mac-1 or p150,95-expressing chinese hamster ovary cell transfectants. Similarly, purified Mac-1 does not support adhesion of ICAM-2 or ICAM-3-expressing L cell transfectants. ICAM-3 on neutrophils does not participate in Mac-1-dependent homotypic aggregation. Thus, ICAM-3 is not a counter-receptor for either Mac-1 or p150,95.

Animals↗

PubMed1996

A monoclonal antibody, 3/22, to rabbit CD11c which induces homotypic T cell aggregation: evidence that ICAM-1 is a ligand for CD11c/CD18.

The rabbit CD11c molecule has been characterized by use of new monoclonal antibody, mAb 3/22. Expression of the p150,95 integrin (CD11c/CD18) has been shown by flow cytometry and immunohistochemistry to be restricted to monocytes, macrophages, dendritic cells and a small population of lymphocytes in peripheral blood. No expression on neutrophils could be demonstrated. Incubation of the newly derived CD8+ T cell line, BJ/873, with mAb 3/22 causes homotypic aggregation, which has been shown to be cell surface event that is not dependent on intracellular signaling or on receptor cross-linking. Inhibition studies show that the ligands responsible for this aggregation are CD11c/CD18 and ICAM-1, both of which are expressed on BJ/873. One other rabbit T cell line, K34, that also expresses p150,95 and ICAM-1, shows a similar aggregation response when stimulated with 3/22. Cell lines that express p150,95 but not ICAM-1 do not aggregate. These observations suggest that ICAM-1 is a ligand for activated p150,95.

Amino Acid Sequence↗

PubMed1996

Phenotypic and functional characterization of CD11c+ dendritic cell population in mouse Peyer's patches.

The antigen-presenting cell system in the gastrointestinal tract, one of three main sites (skin and lung being the others) of primary antigen contact, is poorly understood. Our study focused on dendritic cells (DC) as possible candidates for antigen uptake, processing and presentation in mucosal inductive sites, such as Peyer's patches (PP). To investigate the morphology, immunophenotype and stimulatory activity of intestinal DC, a procedure was developed to obtain a cell population by using collagenase digestion of PP, density centrifugation and cell sorting on the basis of CD11c expression. The resultant low-density cell fraction consisted of a nonadherent cell population expressing different intensities of CD11c that could at least be characterized by typical DC morphology (e.g. abundant cytoplasma with veil-like cytoplasmatic dendrites, irregularly shaped nuclei, multivesicular and multilamellar bodies), constitutive levels of surface MHC class II, the presence of macrophage-specific markers, such as F4/80, Mac-I and Fc receptors, respectively, on subpopulations of CD11c+ sorted cells and expression of adhesion and co-stimulatory receptors like ICAM-1 and CD44. The capability of this low-density CD11c+ fraction to stimulate T cell responses was demonstrated in primary allogeneic mixed-lymphocyte reactions (MLR). Herein, we show that the freshly isolated CD11c+ cells showed weak accessory function, but develop this capacity following short-term culture in vitro in the presence of granulocyte/macrophage colony-stimulating factor. Although the nature and functional capacity of the isolated CD11c+ needs further clarification, these preliminary results describing phenotype and accessory function provide some evidence that these cells isolated from the PP may be immature forms of DC and play a crucial role as antigen-presenting cells with important implications for understanding the complex network regulating intestinal antigen uptake, processing and presentation.

Animals↗