Aspects of the experimental immunopharmacology of oxazaphosphorines.
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Adjuvants, Immunologic↗
Biomedical subjects
S Sozzani
Publications and source records attributed to S Sozzani.
The effect of Biostim (RU 41.740) on natural killer activity in different mouse organs.
The effect of Biostim, a mixture of two glycoproteins extracted from K. pneumoniae, on NK activity in lung, blood and spleen was investigated in mice. Marked increases in NK-cytotoxicity for YAC-1 targets were found after single or repeated administrations of this compound by the i.p. or the oral route in the absence of increases of serum IFN. The highest increases in NK activity were found in lymphoid cells recovered from the lung, active treatments with Biostim significantly increasing the proportion of both target-binding cells and lytic conjugate-forming NK cells. In addition to increasing the rate of clearance from lung and spleen of in vivo-injected radiolabelled YAC-1 cells, short (3 h) exposures to Biostim in vitro augmented the NK-cytotoxicity of murine and human cells. By showing that NK cells can also be a target of Biostim, these results can contribute to a better understanding of the mode of action of this immunomodulator.
Adjuvants, Immunologic↗
Transduction of human MCP-3 by a parvoviral vector induces leukocyte infiltration and reduces growth of human cervical carcinoma cell xenografts.
BACKGROUND: The oncosuppressive properties of some autonomous parvoviruses such as H-1 virus, together with their low pathogenicity, make them attractive vectors for tumor-directed gene therapy. Indeed, it was recently shown that these viruses became endowed with an enhanced oncosuppressive activity after they had been engineered to deliver a recognized therapeutic transgene. This prompted us to use a parvoviral vector to analyse the antineoplastic capacity of MCP-3 (monocyte chemotactic protein-3), a CC chemokine which has a broad spectrum of target cells, and can thus be considered to be a promising candidate for cancer treatment. METHODS: We explored the use of a parvovirus H-1-based vector encoding human MCP-3 for its antitumor potential on human cervical carcinoma cells. HeLa cells were infected in vitro with the recombinant virus hH1/MCP-3 at a low multiplicity [1 replication unit (RU)/cell] and we investigated the effect of parvovirus-mediated MCP-3 transduction on tumor formation and growth upon implantation of HeLa cells in nude mice. RESULTS: Infection of HeLa cells with hH1/MCP-3 led to secretion of high levels of MCP-3 and to significant retardation of tumor growth in recipient mice, as compared with HeLa cells that were either buffer-treated or infected with a MCP-3-free vector. Tumors from hH1/MCP-3-infected HeLa cells were heavily infiltrated with activated macrophages and showed increased numbers of dendritic cells. In addition, activated natural killer (NK) cells were also recruited into MCP-3-transduced tumors. CONCLUSION: These observations indicate that parvovirus H-1-transduced MCP-3 is able to exert a significant antitumor activity which is mediated, at least in part, through macrophages and NK cells, under conditions in which activated T cells are lacking.
Animals↗
Effect of bacterial purified antigenic fractions on natural defence mechanisms.
The in vitro ability of bacterial purified antigenic fractions to interfere with the immune system has been investigated on human mononuclear cells from peripheral blood. Exposure of purified monocytes to the drug at concentrations from 1 to 1000 micrograms/ml, for different periods from 0 to 18 h, significantly increased cell-mediated cytotoxicity against TU5 target cells. Moreover, monocytes exposed for 1 to 18 h to drug concentrations from 0.1 to 1000 micrograms/ml released significant amounts of tumor necrosis factor alpha in a dose-dependent manner in the culture supernatants. The drug was also tested on natural killer (NK) cell activity; mononuclear cells exposed to antigenic fractions for different periods showed a significant increase of NK cytotoxic activity against K562 target cells after 3 and 6, but not 0 and 18 h. Active concentrations were from 1 to 100 micrograms/ml, higher and lower doses being ineffective. Bacterial purified antigenic fractions thus have some ability to interfere in vitro with mechanisms of cytolysis mediated by cells and soluble factors.
Antigens, Bacterial↗
Regulation of chemokine receptor expression in dendritic cells.
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Animals↗
Control of dendritic cell migration by chemokines.
Dendritic cells (DC) are antigen presenting cells able to activate naive T lymphocytes. Immature DC are highly motile and efficiently take up and process antigens. Immature DC localise in non-lymphoid organs where they exert a sentinel function. Upon exposure to immune or inflammatory signals DC undergo maturation and migrate to T cell areas of lymphoid organs. Thus, the correct functioning of DC involves localisation in tissues and trafficking via the lymph or blood to lymphoid organs. Chemokines have emerged as important regulators of DC migration. DC express receptors for and respond to a set of chemoattractants which overlaps with, but is distinct from, that active on other leukocytes. Functional maturation is associated with loss of responsiveness to chemokines present at sites of inflammation and acquisition of a receptor repertoire which renders these cells responsive to signals which guide their localisation in lymphoid organs. A better understanding of the molecular basis of DC trafficking may provide molecular and conceptual tools to direct and modulate DC traffic as a strategy to up-regulate and orient specific immunity.
Animals↗
Role of cellular immunity in the pathogenesis of autoimmune skin diseases.
The pathomechanism of most autoimmune skin diseases is still elusive; however, recent clinical and basic research is leading novel insights into the cellular and molecular biological underlying pathways. Several types of infectious skin diseases are infiltrated by significant number of gamma/delta T cells and similar observations have been made in selected immune-mediated skin conditions. In particular, a role for gamma/delta T cells has been suggested in discoid lupus erythematosus, contact dermatitis, herpetiformis dermatitis, necrotizing cutaneous vasculitis, and cutaneous lesions of systemic sclerosis. The pathogenesis of these diseases is different and this may suggest multiple potential functions of this subset of T cells in the immune system of the skin. Furthermore, most T cells infiltrating tissue and organs undergoing fibrosis have the potential to produce high levels of interleukin 4. This is particularly true for the CD8+ or CD4+ CD8+ double positive T-cell subsets. Furthermore, leukocyte recruitment is a key event in immunity and a better understanding of the signals involved in autoimmune diseases constitutes a valuable basis for the development of new strategies, which control leukocyte migration and function under pathological conditions.
Apoptosis↗
Pro- and anti-inflammatory cytokines: interactions with vascular endothelium.
Cytokines elicit the expression of distinct sets of functions in endothelium. IL-1 activates endothelium in a prothrombotic-proinflammatory sense. The characteristics and significance of IL-1 inducible genes cloned from endothelial cells is discussed.
Cytokines↗
Protein kinase C is not involved in cholesterol-induced resistance to synthetic ether lipids.
The possible role of protein kinase C in cholesterol-induced resistance to ether lipids was investigated. The enrichment of HL60 cells in cholesterol (CHOL) (HL60-CHOL) resulted in a significant increase in the ID50 values for 1-octadecyl-2-methyl-rac-glycero- 3-phosphocholine (ET-18-OMe) (3.75 +/- 0.7 microM and 6.69 +/- 0.5 microM for HL60 and HL60-CHOL, respectively). In the same conditions, HL60 and HL60-CHOL cells showed comparable levels of both cytosolic and membrane-associated protein kinase C activity. Phorbol ester (PMA) stimulation induced protein kinase C to translocate from the cytosol to the plasma membrane in both cell types and with similar kinetics (272 +/- 32% and 299 +/- 41% increase in HL60 and HL60-CHOL, respectively after 100 ng/ml PMA for 10 min). Pretreatment of the two cell types with 50 microM ET-18-OMe resulted in comparable levels of PKC inhibition after phorbol ester stimulation. These results suggested that alterations in plasma membrane lipid composition induced by CHOL do not result in major changes in protein kinase C activity. Thus, protein kinase C does not appear to be involved in cholesterol-induced resistant phenotype in HL60 cells.
Cholesterol↗