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PubMed2005

Identification of classical swine fever virus protein E2 as a target for cytotoxic T cells by using mRNA-transfected antigen-presenting cells.

Vaccination of pigs against Classical swine fever virus (CSFV) by using live-virus vaccines induces early protection before detectable humoral immune responses. Immunological analyses indicate that this is associated with T-cell activation, underlining the importance of targeting cytotoxic T-lymphocyte (CTL) responses for vaccine improvement. Antigen-presenting cells (APCs) transfected with mRNA encoding structural protein E2 or non-structural viral proteins NS3-NS4A were used to identify viral genes encoding CTL epitopes. Monocyte-derived dendritic cells (DCs) and fibrocytes served as the APCs. In vitro translation of the mRNA and microscopic analysis of transfected cells demonstrated that E2 and NS3-NS4A could be identified. APCs transfected with either of the mRNA molecules restimulated CSFV-specific T cells to produce gamma interferon and specific cytotoxic activity against CSFV-infected target cells. The presence of CTL epitopes on E2 was confirmed by using d/d-haplotype MAX cells expressing E2 constitutively as target cells in d/d-haplotype CTL assays. A potent CTL activity against E2 was detected early (1-3 weeks) after CSFV challenge. This work corroborates the existence of CTL epitopes within the non-structural protein domain NS3-NS4A of CSFV. Furthermore, epitopes on the E2 protein can also now be classified as targets for CTLs, having important implications for vaccine design, especially subunit vaccines. As for the use of mRNA-transfected APCs, this represents a simple and efficient method to identify viral genes encoding CTL epitopes in outbred populations.

Animals↗

PubMed1997

The interplay between primary and secondary cytokines. Cytokines involved in the regulation of monocyte recruitment.

Cytokines and chemokines play significant roles in the recruitment of leucocytes from the circulation and are therefore crucial determinants of inflammatory reactions and immunity. As knowledge of the actions of these agents and their regulatory mechanisms increases, so does the opportunity to devise pharmacological means of intervening in the activities of these molecules. It is now believed, for instance, that the actions of the classical pro-inflammatory cytokine interleukin (IL)-1 are inhibited by the expression and presentation of a 'decoy' receptor, which acts as a 'molecular trap' for IL-1. There is evidence to suggest that IL-6, formerly considered a purely anti-inflammatory cytokine, also has proinflammatory properties. Furthermore, regulation of the chemokine system, which can be achieved by regulating agonist production or altering the expression of chemokine receptors, has recently been demonstrated. These and other new findings, which may prove to have considerable relevance as regards current or future strategies for the treatment of inflammation, infection, neoplasia etc., are presented and discussed in this article.

Chemokine CCL2↗

PubMed1988

Primary culture of cryopreserved adult human hepatocytes on homologous extracellular matrix and the influence of monocytic products on albumin synthesis.

Cultured human hepatocytes provide a useful method for studies of specific metabolic functions, such as plasma protein synthesis or drug metabolism in man and specific interaction of microorganisms with the human liver cell. In vitro studies using human hepatocytes are seriously hampered by the limited availability of viable tissue and the lack of suitable methods for preservation of hepatocytes. In addition, normal adult human hepatocytes, under classical culture conditions, do not proliferate in vitro. Recently, we have reported a method for long-term storage of human hepatocytes, using a cryopreservation technique. However, after thawing, the efficiency of cell seeding onto tissue culture plastic and, accordingly, the survival of hepatocytes in primary cultures were decreased as compared to freshly prepared and cultured hepatocytes. In the present study, we report the effects of extracellular matrix (ECM) obtained from normal liver of kidney donors on the attachment efficiency, survival, some metabolic functions and fine structure of human hepatocytes. It was found that the deleterious effect of deep-freeze storage on attachment efficiency and survival of hepatocytes could be significantly reduced by using tissue culture plastic precoated with human liver ECM. Hepatocytes survived for more than 4-6 weeks, without evidence of fibroblast overgrowth. Using this in vitro experimental system, we have also shown that these hepatocytes synthesize several liver-specific acute phase proteins, and monocytic products were able to decrease the hepatocytic synthesis of albumin while total protein synthesis remained unchanged. These results support our previous observations in cultured rodent hepatocytes, indicating the important role of monocytic products in the regulation of liver synthesis of albumin in inflammatory diseases in man.

Albumins↗

PubMed2006

RhoA mediates angiotensin II-induced phospho-Ser536 nuclear factor kappaB/RelA subunit exchange on the interleukin-6 promoter in VSMCs.

The vasoconstrictor angiotensin II (Ang II) accelerates atherosclerosis by inducing vascular gene expression programs, producing monocyte recruitment, and vascular remodeling. In vascular smooth muscle cells (VSMCs), Ang II signaling activates interleukin (IL)-6 expression, a cytokine producing acute-phase inflammation, mediated by the transcription factor nuclear factor kappaB (NF-kappaB). The classical NF-kappaB activation pathway involves cytoplasmic-to-nuclear translocation of the potent RelA transactivating subunit; however, because nuclear RelA is present in VSMCs, the mechanism by which NF-kappaB activity is controlled is incompletely understood. In this study, we focus on early activation steps controlling RelA activation. Although Ang II only weakly induces approximately 1.5-fold RelA nuclear translocation, RelA is nevertheless required because short interfering RNA-mediated RelA knockdown inhibits inducible IL-6 expression. We find instead that Ang II stimulation rapidly induces RelA phosphorylation at serine residue 536, a critical regulatory site in its transactivating domain. Chromatin immunoprecipitation assays indicate no significant changes in total RelA binding to the native IL-6 promoter, but an apparent increase in fractional binding of phospho-Ser536 RelA. Inactivation of RhoA by treatment with Clostridium botulinum exoenzyme C3 exotoxin or expression of dominant negative RhoA blocks Ang II-inducible RelA Ser536 phosphorylation and IL-6 expression. Finally, enhanced phospho-Ser536 RelA formation in the aortae of rats chronically infused with Ang II was observed. Together, these data indicate a novel mechanism for Ang II-induced NF-kappaB activation in VSMCs, mediated by RhoA-induced phospho-Ser536 RelA formation, IL-6 expression, and vascular inflammation.

Angiotensin II↗

PubMed2005

Isolevuglandins, oxidatively truncated phospholipids, and atherosclerosis.

Isolevuglandins (isoLGs) and oxidatively truncated phospholipids are products of lipid peroxidation. Some of these, especially isoLGs and gamma-hydroxyalkenal analogues (e.g., the 5-hydroxy-8-oxo-6-octenoic acid and 9-hydroxy-12-oxo-10-dodecenoic acid esters of 2-lysophosphatidylcholine, HOOA-PC or HODA-PC, respectively) of 4-hydroxy-2(E)-nonenal (HNE), damage proteins by covalent adduction, thereby interfering with their normal functions. These lipid-derived protein modifications may serve as dosimeters of oxidative injury. Elevated plasma levels of isoLG-protein epitopes are associated with atherosclerosis but are independent of total cholesterol, a classical risk factor. Both protein adducts and oxidatively truncated phospholipids (oxPL) can also elicit receptor-mediated cellular responses that include endocytosis of oxidized low-density lipoprotein (LDL) and expression of chemokines, which may foster infiltration of monocyte macrophages into the subendothelial space, where they become foam cells through unregulated endocytosis of oxidatively damaged LDL.

Arteriosclerosis↗

PubMed2002

Heat shock protein 70 is a potent activator of the human complement system.

According to new hypotheses, extracellular heat shock proteins (Hsps) may represent an ancestral danger signal of cellular death or lysis-activating innate immunity. Recent studies demonstrating a dual role for Hsp70 as both a chaperone and cytokine, inducing potent proinflammatory response in human monocytes, provided support for the hypothesis that extracellular Hsp is a messenger of stress. Our previous work focused on the complement-activating ability of human Hsp60. We demonstrated that Hsp60 complexed with specific antibodies induces a strong classical pathway (CP) activation. Here, we show that another chaperone molecule also possesses complement-activating ability. Solid-phase enzyme-linked immunosorbent assay was applied for the experiments. Human Hsp70 activated the CP independently of antibodies. No complement activation was found in the case of human Hsp90. Our data further support the hypothesis that chaperones may messenger stress to other cells. Complement-like molecules and primitive immune cells appeared together early in evolution. A joint action of these arms of innate immunity in response to free chaperones, the most abundant cellular proteins displaying a stress signal, may further strengthen the effectiveness of immune reactions.

Complement Pathway, Classical↗

PubMed2002

Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion.

Heat shock protein 70 (Hsp70) is an antiapoptotic chaperone protein highly expressed in human tumors. Here we demonstrate that locoregional application of adenovirus expressing antisense Hsp70 cDNA (Ad.asHsp70) eradicates orthotopic xenografts of glioblastoma and breast carcinoma, as well as s.c. xenografts of colon carcinoma in immunodeficient mice. Ad.asHsp70-treated tumors showed massive apoptosis-like cell death and recruitment of macrophages. Human monocyte-derived macrophages effectively removed the corpses of Ad.asHsp70-treated tumor cells in vitro. Interestingly, both tumor cell death and phagocytosis were caspase-independent. Thus, Hsp70 appears as a promising target for the treatment of cancers resistant to classic caspase-mediated apoptosis.

Adenoviridae↗

PubMed1985

Identification of anti-DQ alloantisera correlated with DR5.

Using classical serological methods, we have been able to distinguish anti-HLA-DR from anti-DQ antibodies. The specificity of alloantisera for DQ could be identified on the basis of differential reactivity against B cell and monocyte-enriched leucocyte suspensions and lack of inhibition of cytotoxicity by anti-DR monoclonal antibodies. Some alloantisera, whose reactivity was significantly correlated with DR5, were found to exhibit these characteristics. The suggestion that they recognize DQ specificities in linkage disequilibrium with DR5 was supported by immunochemical analysis.

Antibodies, Monoclonal↗

PubMed1990

Identification of a novel integrin beta subunit expressed on cultured monocytes (macrophages). Evidence that one alpha subunit can associate with multiple beta subunits.

The vitronectin receptor (VnR) is one member of a subset of cell adhesion receptors within the integrin supergene family which shares the beta 3 subunit (IIIa). We show here that the VnR is absent from the surface of monocytes freshly isolated from blood but is expressed on these cells after a period of in vitro culture. Such cultured monocytes (macrophages) from a patient with type I Glanzmann's thrombasthenia, however, failed to express the VnR. Instead, immunoprecipitation with a monoclonal antibody directed to the VnR alpha chain (alpha v) revealed a novel integrin comprising alpha v associated noncovalently with a 100-kDa beta subunit (beta 3b), immunologically unrelated to the VnR beta subunit (beta 3a). This same novel integrin complex was also identified on 10-day-old macrophages from healthy donors, but on these cells, the beta 3b subunit was co-expressed with the classical VnR complex of alpha v beta 3a. The novel beta 3b subunit was not identified by monoclonal or polyclonal antibodies to IIIa (beta 3a) nor by a monoclonal antibody to the classical VnR complex. The beta 3b subunit could be distinguished from beta 3a by its relatively greater migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis after reduction, by its distinct isoelectric point upon two-dimensional gel electrophoresis, and by one-dimensional peptide mapping. Neither platelets nor B lymphoblasts from this patient with Glanzmann's thrombasthenia expressed any VnR on their surface, whereas control cells from a normal donor expressed the classical VnR but not the beta 3b subunit. The two beta chains, and hence also the combined receptor complexes, appeared to be differentially regulated. These findings provide the first example of an integrin alpha chain complexed with more than a single beta chain in the same cell. Furthermore, the differential regulation of expression of the different beta subunits that associate with the VnR alpha chain on cultured monocytes suggests a role for the novel receptor complex during monocyte/macrophage differentiation.

Adult↗

PubMed1986

Sensitization with Fusobacterium nucleatum targets antibody-dependent cellular cytotoxicity to mammalian cells.

Incubation of mammalian tumor cells with either soluble of insoluble fractions (10 to 100 micrograms/ml) of Fusobacterium nucleatum sensitizes them to the destructive activity of antibody-dependent cellular cytotoxicity (ADCC) effector cells in the presence of anti-F. nucleatum antisera. All three types of ADCC effector cells are capable of destroying F. nucleatum-sensitized target cells with varying degrees of effectiveness (lymphocytes much greater than monocytes greater than neutrophils). Hyperimmune rabbit anti-F. nucleatum antisera were active at a dilution as high as 1/100,000. Our studies indicated that F. nucleatum must be bound to the target cells since if either the effector cells are treated with F. nucleatum or F. nucleatum is directly to an ADCC reaction, there is no significant effect on cytotoxicity. The kinetics of F. nucleatum-targeted ADCC are identical to those of classical ADCC, suggesting a similar mechanism. The specificity of F. nucleatum-targeted ADCC was demonstrated by cold target inhibition studies and by showing that other antibacterial antisera were incapable of mediating the activity.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1992

Change in the frequency of apoptosis after low- and high-dose X-irradiation of human lymphocytes.

The purpose of the present study was to correlate the type and frequency of cell death in human lymphocytes receiving variable doses of X-irradiation. Monocyte-depleted lymphocyte fractions were exposed in vitro to variable doses of X-rays of 0-20 Gy (0-2000 rads) and incubated for 4 and 16 h. An assessment of the mode of cell death (apoptosis vs. classical necrosis) was carefully evaluated using a multidisciplinary approach using light, fluorescence and electron microscopy (EM), and dye exclusion assays. Eosin Y exclusion assays indicated the absence of classical necrosis occurring in short-term cultures (4 h postirradiation). An assessment of cell counts, however, revealed a mean decrease of 4% at 0 Gy and 13% at 10-20 Gy (1000-2000 rads). The predominant mode of cell death was apoptosis, but the percent apoptotic cells (determined by EM) did not parallel this increase in cell loss with increasing radiation and actually decreased at doses above 5 Gy (500 rads). The discrepancy between percent cell loss and percent apoptosis was explained by a proposed change in overall duration of the apoptotic process. In long-term cultures (16 h postirradiation), a combination of classical necrosis, classical apoptosis, and combined apoptosis and necrosis (secondary necrosis of apoptotic cells) was apparent and was associated with a marked decrease in viability. Irradiation effects on lymphocytes showing none of the morphologic features of apoptosis or classical necrosis in short-term culture were evidenced by an increase in nuclear lobation. The results of this study indicate that the vast majority of peripheral blood lymphocytes are radioresistant. The use of irradiation in an in vitro model to study the biochemical events of the apoptotic process is also evaluated.

Apoptosis↗

PubMed1994

Expression of the CEA gene family members NCA-50/90 and NCA-160 (CD66) in childhood acute lymphoblastic leukemias (ALLs) and in cell lines of B-cell origin.

The carcinoembryonic antigen (CEA) and the classical non-specific cross-reacting antigens (NCAs) belong to the CEA gene family which is part of the immunoglobulin superfamily. In normal hematopoiesis, CEA gene family members (CGMs) have only been reported on cells of myeloid and monocytic origin. In the present study, we analyzed 62 childhood acute lymphoblastic leukemias (ALLs) and seven surface immunoglobulin positive (sig+) B-cell lines for the expression of the CEA family members CEA, NCA-50/90, NCA-95, NCA-160, CGM1 and CGM7. We demonstrated that members of the CEA family were present in 76% of childhood ALLs of B- and T-cell origin. In ALLs of B-cell origin, 82% of the samples expressed at least one CEA subgroup member: 38% NCA-50/90 (CD66c), 31% NCA-160 (CD66a), and 13% both. Six of seven B-cell lines solely expressed NCA-160. In seven ALL of T-cell origin, sole NCA-160 expression was present in 29% of the cases. CEA and CGM1 were not expressed in childhood ALLs or in the sIg+ B-cell lines. In 15 ALLs and seven B-cell lines which could be analyzed for CGM7 expression, the antigen was not detected. NCA-95 was not expressed in 91% of the B-lineage ALLs, in T-lineage ALLs and in the B-cell lines. However, five B-lineage ALLs showed conflicting data on the binding patterns of two, on leukocytes specifically NCA-95 recognizing antibodies suggesting either expression of unknown forms of NCA-95 or NCA-50/90 or of a yet unknown member of the CEA family in these ALL cells. The expression of CEA subgroup members in childhood ALL cells might have prognostic impacts, as an inverse correlation exists between NCA expression on leukemic blasts and the risk factor white blood count at diagnosis.

Adolescent↗

PubMedDate not supplied

Acute promyelocytic leukemia: morphological and clinical features.

BACKGROUND AND METHODS: Acute promyelocytic leukemia (APL) is not a morphologically homogeneous entity: to verify whether there is any relationship between this heterogeneity and other biological and clinical aspects, we studied 43 cases of APL with morphological, cytochemical, cytogenetic and immunological methods. RESULTS: Three morphological categories were present: a classic hypergranular type (30 cases), a microgranular type (6 cases) and a form with basophilic granules (M3b) that stained metachromatically with toluidine blue (7 cases). In all these groups there were cases with cytochemical features of both myeloid and monocytic type (alpha-naphthyl-acetate esterase positive). No immunological and cytogenetic differences were observed; the morphological variant with basophilic granules was more frequent in females; age distribution was not related to the morphological subtype; organomegaly was extremely rare in M3b. A low white blood cell count was constant in M3b, whereas no differences were observed in hemoglobin and platelet values. Severity of bleeding was worst in the group with toluidine blue metachromasia; this and the microgranular type had poor prognosis. CONCLUSIONS: Our study confirms the importance of identifying different cytologic categories in APL. In particular we focused our attention on a new variant with basophilic granules.

Adolescent↗

PubMed1998

Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation.

We have previously shown that an anticoagulant could attenuate inflammation in animal models of sepsis with disseminated intravascular coagulation (DIC) and that coagulation activation of human whole blood ex vivo results in a proinflammatory cytokine response. The current studies were performed to better understand mechanisms for the blood cell cytokine response and extend the investigation of such a response to endothelial cells as likely contributors to a vascular inflammatory response. Utilizing cell separation techniques, it was determined that the whole blood IL-8 response to coagulation activation or thrombin, specifically, was mediated by CD14+ monocytes. Moreover, thrombin was observed to stimulate both IL-8 and IL-6 production in cultured mononuclear cells. Analyses of the effects of coagulation activation and thrombin were extended to cultured human endothelial cells, and a similar cytokine response was observed. Thrombin catalytic activity appeared essential, since hirudin reduced thrombin-stimulated proinflammatory cytokine production in cultured monocytes and endothelial cells and prothrombin only weakly mimicked the thrombin response. The endothelial cell IL-8 and IL-6 response to thrombin could be mimicked by the thrombin receptor agonist peptide (TRAP), implicating a functional role of the classic thrombin receptor. Altogether, the results facilitate a better understanding of potential proinflammatory vascular responses to coagulation activation.

Blood Coagulation↗

PubMed1989

Engulfment of the Philadelphia strain of Legionella pneumophila within pseudopod coils in human phagocytes. Comparison with other Legionella strains and species.

In this paper we report our ultrastructural studies of the early phagocytosis of two different strains of L. pneumophila serogroup (SG) 1 (Philadelphia 1 and Knoxville 1) and of L. micdadei. These bacteria replicate, in vivo as well as in vitro, in eukaryotic cells e.g. in monocytes and macrophages. Whether or not the mode of entry of these organisms in phagocytes contributes to their intracellular survival is presently unknown. Whilst internalization of bacteria of the Philadelphia 1 strain occurred within a pseudopod coil, organisms of the Knoxville 1 strain and L. micdadei were phagocytized in the classical manner, i.e. between pseudopods. No ultrastructural differences were observed between the two strains of L. pneumophila SG 1 whereas L. micdadei appeared as shorter rods with an extracellular layer of relatively low electron density. The phenomenon of coiling phagocytosis was not affected by heat-killing the bacteria or preopsonization with specific antibody. Formation of phagolysosomes was seen when cells of the Knoxville strain and L. micdadei were used but not with the Philadelphia strain. In our experiments, the occurrence of coiling phagocytosis was specific for the Philadelphia 1 strain of L. pneumophila and independent of bacterial virulence. Thus, it seems most unlikely that the coiling phenomenon plays any important role in the resistance of Legionella to the killing abilities of phagocytic cells.

Humans↗

PubMed1977

Rosetting and other reactions of the Reed-Sternberg cell.

Clustering of lymphocytes around Reed-Sternberg cells was noticed in single cell suspensions made from viable Hodgkin's lymphoid tissue. Cytocentrifugation of the suspension showed that clustering also occurred around a smaller cell type, thought to be the precursor of the classical Reed-Sternberg cell. Time-lapse cine films taken of the clustering showed unceasing activity on the part of the lymphocytes migrating over the surface of the central cell. Reed-Sternberg cells were reacted with anti-monocyte serum using indirect fluorescence techniques. In its mature form at least, the Reed-Sternberg cell showed no activity with the antiserum. No immunoglobulin was detected in the Reed-Sternberg cell using fluorescence techniques, but a few Reed-Sternberg cells showed diffuse cytoplasmic staining using the peroxidase-labelled antibody technique. Membrane receptor tests showed the lymphocytes surrounding the Reed-Sternberg cell to be T-cells. After proteolytic enzyme treatment to free lymphocytes from the surface, the Reed-Sternberg cell bound IgG-coated red blood cells indicating a probable Fc receptor. Cytochemistry demonstrated weak non-specific esterase activity in a small minority of Reed-Sternberg cells, and absence of acid phosphatase, alkaline phosphatase and peroxidase. A subpopulation of lymphocytes with distinctive segmentation of the nucleus was noted. These were often to be seen participating in lymphocyte rosettes around the Reed-Sternberg cell.

Cells, Cultured↗

PubMed1996

[Role of plasmalemma in the process of aging, elimination and reproduction of erythrocytes: plasmalemmal microvesicles as stimulators of erythropoiesis].

This study summarizes the experimental findings suggesting that plasmalemmal microvesicles formed from red blood cell aging are stimulators of erythropoiesis. The supposed sequence of events consists of microvesicular absorption by the settled macrophages of the liver and spleen, a message of information from circulatory monocytes (and lymphocytes) to the central macrophage of erythropoietic islands and regulation of late erythropoiesis. This is an autoerythronic regulation because it corrects red blood cell reproduction in relation to the rate of cell aging and thus differs from the classical humoral type which regulates erythrocytic reproduction according to visceral oxygen supply.

Animals↗

PubMed2005

Evolution of T lymphocytes and cytokine expression in classical swine fever (CSF) virus infection.

This study characterized the cell-mediated immune response in pigs inoculated with the Alfort 187 isolate of classical swine fever (CSF) virus. Quantitative changes in the T-lymphocyte population (CD3(+), CD4(+) and CD8(+)) and qualitative changes in cytokine expression (IL-2, IL-4 and IFNgamma) by these cells in serum, thymus and spleen were demonstrated. These changes coincided spatially and temporally with previously described quantitative and qualitative changes in monocyte-macrophage populations, thus demonstrating the contribution of the two cell populations to lymphoid depletion. Moreover, examination of cytokine expression in thymus and spleen samples revealed a type 1 cell-mediated immune response in the early and middle stages of the experiment, giving way to a type 2 immune response towards the end of the experiment; these findings, which accorded with the serological results and lymphopenia, may influence the delayed humoral response characteristic of CSF.

Animals↗