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Biomedical subjects

F Dianzani

Publications and source records attributed to F Dianzani.

At least 109 records · Page 6Linked to original sources

Alpha interferon treatment in HIV infected patients restores gamma interferon production in vitro.

We studied gamma interferon (IFN) production in vitro by lymphocytes from 5 patients with AIDS and 2 with advanced AIDS-related complex (ARC) before and during treatment with r-alpha 2a IFN at low doses, for up to 12 months. Patients were divided in responders (three) and non responders according to clinical data after six months of treatment. No immunological parameter was predictive of the clinical results. We found that subpopulations of T lymphocytes and lymphoproliferative response were not significantly modified in responders, while severely decreased in non responder patients. In 5/7 cases we observed a small but significant increase of gamma IFN production after six months of therapy, which rose to normal values after 12 months in responders.

AIDS-Related Complex↗

Low incidence of neutralizing antibody formation to interferon-alpha 2b in human recipients.

Patients receiving large amounts of interferon (IFN), particularly cloned IFN-alpha, have been reported to develop antibodies to IFN-alpha. We used a neutralization technique bioassay to monitor 175 patients undergoing recombinant (r) IFN-alpha 2b therapy in an attempt to correlate antibody production to disease progression. Only 1 patient being treated for chronic myelogenic leukemia produced antibodies. Our findings indicate that rIFN-alpha 2b has minimal antigenicity, even when administered for prolonged periods of time.

Adolescent↗

Acid-labile human interferon alpha production by peripheral blood mononuclear cells stimulated by HIV-infected cells.

We compared the properties of interferon (IFN) induced in peripheral blood mononuclear cells (PBMC) by free infectious HIV to that induced by HIV-infected cells fixed with glutaraldehyde. While the IFN induced by HIV was a conventional IFN alpha, the IFN induced by HIV-infected cells, although sharing with IFN alpha both antigenic properties and molecular weight, was strongly inactivated by treatment at pH lower than 4. The ability to induce acid-labile IFN alpha was exerted both by the chronically-infected cell line H9/HIV and by normal PBMC infected in vitro with HIV, while infection of inducers cells with viruses other than HIV made these cells capable of inducing only acid-stable IFN alpha. The cell involved in the production of this type of IFN seems to be B-lymphocyte. Because the presence of acid-labile IFN alpha in the serum of AIDS patients has been described, we suggest that this unusual IFN derives from interaction between circulating B-lymphocytes and the HIV-infected cells.

Acquired Immunodeficiency Syndrome↗

Differences in the mechanism of induction of interferon-alpha by herpes simplex virus and herpes simplex virus-infected cells.

The cellular source of IFN alpha after induction with Herpes simplex virus type-1 (HSV) and HSV-infected fibroblasts was investigated by using human peripheral blood mononuclear cell (PBMC) populations, purified according to conventional procedures, and which included T- and B-lymphocytes as well as monocytes. It appears that the cells responding to HSV virions are monocytes, whereas the PBMC population induced by HSV-infected cells is represented by B-lymphocytes. Furthermore, by using monoclonal antibody (MoAb) to HLA class I and class II products, it appears that different membrane structures are involved in the induction of IFN by HSV virions, as opposed to HSV-infected cells. In fact, most anti-HLA class II MoAbs inhibit IFN induction by HSV-infected cells, and not IFN induction by HSV virions.

Antibodies, Monoclonal↗

A macrophage-derived factor different from interleukin 1 and able to induce interferon-gamma and lymphoproliferation in resting T lymphocytes.

A novel monokine different from interleukin 1 (IL-1) is secreted from human or murine macrophages stimulated with galactose oxidase, a well-characterized enzyme able to induce marked polyclonal activation of lymphocytes. This monokine, preliminarly termed macrophage-derived blastogenic factor (MBF), stimulates resting T lymphocytes to produce interferon (IFN)-gamma and to proliferate. The apparent MW of MBF ranges between 29,000 and 35,000, although some active fractions show smaller MW ranging from 2000 to 7000, as demonstrated by gel filtration. The biological relationship between MBF and IL-1 was examined and it was found that MBF (1) is able to induce IFN-gamma production and proliferation by T lymphocytes in the absence of other inducers, (2) is not able to activate PHA-stimulated C3H mouse thymocytes, (3) is not able to induce production of IFN-beta by fibroblast cultures, (4) is resistant to proteolytic enzymes, and (5) is not neutralized by antibodies to IL-1. MBF was released in the macrophage supernatants in two waves after the oxidation process, namely, after 15 min and 2.5 hr, and each wave was capable of inducing lymphocyte activation at dilutions up to 1:32. Because the oxidation of galactose residues on cell surface structures is considered a general feature of lymphocyte activation whatever the inducer, it seems that MBF may be a mediator involved in mitogenic activation of T cells leading to IFN-gamma production and proliferation.

Animals↗

Mechanism of human interferon-gamma production: involvement of beta-2-microglobulin.

The ability of several monoclonal antibodies (MoAbs) against beta-2-microglobulin (beta 2m) to inhibit interferon-gamma (IFN) production was assayed in peripheral blood mononuclear cells (PBMC). All of them strongly reduce IFN-gamma induction by galactose oxidase (GO), a well-characterized enzyme capable of activating T lymphocytes through mediation of macrophages. In contrast, many MoAbs directed against HLA class I (heavy chain) and class II antigens do not inhibit IFN induction by GO. On the other hand, anti-beta 2m MoAbs do not effectively reduce IFN-gamma induction by A23187, a calcium ionophore that acts on T cells in the absence of accessory cells. Competition experiments demonstrate that (i) the inhibition of anti-beta 2m antibodies was specific for beta 2m protein, and (ii) beta 2m is not itself the site of action of GO. Moreover, it is demonstrated that the addition of beta 2m to oxidated PBMC strongly enhances subsequent IFN-gamma production. Oxidation of galactose residues on glycoproteins of macrophage membrane is an obligate step for IFN-gamma induction whatever the inducer, thus our results suggest that beta 2m is involved in the mechanism of induction of IFN-gamma.

Antibodies, Monoclonal↗

Early steps in interferon-gamma production: possible involvement of Ca2+-calmodulin-dependent enzymes.

A23187 in combination with phorbol myristate acetate (PMA) strongly induces production of interferon-gamma (IFN-gamma) by human peripheral blood mononuclear cells (PBMC) and even by murine PBMC, which respond poorly to A23187 alone. Macrophage depletion of PBMC strongly reduces IFN-gamma production induced by several mitogens, but does not affect IFN-gamma production induced by A23187 and PMA. In addition the same stimuli are able in combination to induce strong amounts of IFN-gamma, even in the Jurkat T cell line. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and the calmodulin antagonist N-(6-aminoehexyl)-5-chloro-1-naphthalenesulfonamide (W-7) were examined for their ability to inhibit IFN-gamma production induced by PMA and A23187. At concentrations near the Ki for protein kinase C, H-7 failed to inhibit PMA- and A23187-induced IFN-gamma production. In contrast, W-7 at low concentrations inhibited IFN-gamma production induced by the same stimuli. In addition OAG, which is known to directly activate protein kinase C, failed to act synergistically with A23187 in the induction of IFN-gamma. On the basis of these results we propose that A23187 and PMA may mimic the early steps of lymphocyte activation, without the requirement of macrophage, bypassing antigen-, or lectin-induced signal. Our results suggest that Ca2+-calmodulin-dependent reactions other than protein kinase C activation may be essential for IFN-gamma production, at least at level of the producing cells.

Animals↗

Evidence that defective gamma interferon production in patients with primary immunodeficiencies is due to intrinsic incompetence of lymphocytes.

We have selected 11 patients with primary immunodeficiency disorders predominantly affecting T lymphocyte function (four with ataxia-telangiectasia (AT), four with common variable immunodeficiency (CVI) and one each with Wiskott-Aldrich syndrome, hyper-IgE syndrome and combined immunodeficiency) with defective gamma interferon (IFN-gamma) production in vitro. Induction with phytohaemagglutinin showed low interleukin 2 (IL-2) production concomitant with reduced IFN-gamma titres. However the addition of 10 U/ml of rIL-2 to cultures stimulated with staphylococcal enterotoxin B or galactose oxidase failed to restore IFN-gamma production in defective cases. IFN-gamma was titrated by both bioassay and immunoradiometric assay, ruling out the possible release of inactive or altered IFN-gamma molecules. Normal levels of IFN-gamma were found in patients of patients with AT, as well as in two AT and two CVI cases, demonstrating heterogeneity of defects within these syndromes. Soluble inhibitors or cellular suppression of IFN-gamma were not observed in mixing experiments. The possibility that defective interaction between accessory cells and T lymphocytes might account for the poor response to the inducing agents was ruled out as no IFN-gamma was produced using a calcium ionophore--which bypasses this step--in seven patients with absolute IFN-gamma deficiency.

Ataxia Telangiectasia↗

Membrane interactions involved in the induction of interferon-alpha by Mycoplasma pneumoniae.

Interferon (IFN) induction by Mycoplasma pneumoniae (MP) in human peripheral blood mononuclear cells (PBMC) has been studied. We show that IFN yields depend on the concentration of both lymphocytes and MP. The effective IFN inducer appears to be the mycoplasma membrane, and IFN production occurs without significant lymphocyte proliferation. Data obtained by both positive and negative selection experiments suggest that the PBMC subpopulation induced by MP is B lymphocyte, as opposed to the main subpopulation induced by NDV that is monocyte. Evidence is also provided suggesting that the membrane interaction between MP and the B cells is mediated by MHC Class II antigens.

B-Lymphocytes↗

Inhibition of contact sensitivity to oxazolone by the calmodulin inhibitor trifluoroperazine.

Topical application of trifluoroperazine (TFP), a calmodulin inhibitor, on the skin of CBA mice previously immunized with 2-phenyl-4-ethoximethylene-oxazolone (oxazolone) blocks the expression phase of contact sensitivity. More detailed analysis of the TFP-mediated inhibition of contact sensitivity shows that TFP significantly suppresses the passive transfer of contact sensitivity when added in vitro to oxazolone-immune cells at a molar concentration of 10(-4) -10(-5). Furthermore, the DNA synthesis of draining lymph node cells from immune mice challenged with oxazolone was suppressed when cultured in the presence of TFP. The exposure of spleen and lymph node cells from immune animals to recombinant IL-2 fails to modify the TFP-mediated inhibition of passive transfer and cell proliferation. The TFP topical application opens the possibility to use this compound in the treatment of delayed hypersensitivity-caused skin disorders.

Administration, Topical↗

Pharmacokinetics of recombinant interferon-alpha 2 following intralesional administration in malignant glioma patients.

Pharmacokinetics of recombinant interferon-alpha 2 (rIFN-alpha 2) following intralesional administration into patients with malignant gliomas was investigated. A dose of 5 X 10(6) IU of rIFN-alpha 2 was injected locally postoperatively for 2 weeks each day, and the same dose was then given once a week for 10 additional weeks. During the daily and weekly administration, the IFN was consistently present in the fluid of the postsurgical cavity. Not until 5 weeks after the end of the IFN administration was the IFN undetectable. The decay of IFN injected was minimal.

Adult↗

Influence of monoclonal antibodies against HLA class I and class II antigen on interferon-gamma and -alpha induction.

The effects of several monoclonal antibodies (MAbs) directed against different epitopes of HLA class I and class II antigens on interferon (IFN)-gamma and IFN-alpha production were studied. The results indicate that: these MAbs have a marked inhibitory effect on the production of IFN-gamma induced by alloantigens and microbial antigens; they influence only to a lesser extent staphylococcal enterotoxin B (SEB)- and phytohemagglutinin (PHA)-induced IFN-gamma production; such effects parallel inhibition of lymphoproliferation except for PHA-induced blastogenesis, which is not affected; on the other hand, these MAbs have no effect on the production of IFN-alpha induced by lipopolysaccharide (LPS) or viruses.

Adult↗

Interferon review.

Although IFN proteins were recognized first for their potent antiviral properties, it has now been established that they may profoundly affect other vital cellular functions. The IFNs are divided into three main classes, alpha, beta, and gamma, and are defined by their differences in amino acid sequences, physicochemical properties, and induction by different agents from different cell types. The inducing agents include viruses, bacteria, bacterial products, polymers, low molecular weight compounds, and antigens or mitogens. Studies on the mechanisms of action of IFNs have mainly been focused on their antiviral actions. However, many of the facts revealed by these studies are equally relevant for understanding other actions of IFN. IFNs are extremely potent, they interact with specific receptors, and they induce the expression of specific genes, the products of which mediate their various actions. There is almost a complete lack of knowledge of what happens between the interaction of IFN with its receptor and induction of new RNA synthesis. However, we are beginning to understand how some of the IFN-inducible enzymes impair viral replication. The discovery of the dsRNA-dependent enzymes has implications beyond the IFN system. It is quite possible that they are used for other physiologic regulatory systems as well. The identities and functions of many other IFN-inducible proteins remain to be elucidated. Principally, IFNs alpha and beta are cytokines in that they may be produced by the cellular components of the immune system and have immunoregulatory effects on the cells of the immune system. These effects include enhancement of surface structures such as histocompatibility antigens, pleiotropic hormone-like effects, and stimulation or inhibition of the activities of a number of different effector cells such as B cells, T cells, macrophages, and natural killing cells. IFN levels may be below detection and yet mediate important biologic functions. Perhaps the most interesting IFN subtype regarding immunoregulation is IFN gamma, which is a product of T lymphocytes. Few drugs have stimulated as much research interest or clinical promise as the IFNs. Clinical trials in patients have shown most promise in coryza, herpes virus infections, papilloma virus tumors, hairy cell leukemia, multiple myeloma, and renal cell carcinoma. IFN gamma employed alone and in combination with IFN alpha may dramatically increase IFN's activity. IFN treatment combined with chemotherapy also may give enhanced antitumor activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

The Italian National Research Council and hospital infections.

In 1983 the Italian National Research Council funded a project specifically focused on Hospital infection control. The main objectives were to describe the epidemiological pattern of hospital-acquired infections; to evaluate different control measures and preventive strategies. The general frame and research issues of the project are discussed in this paper. The main research areas of the project were: urinary tract infections; infections in surgery; intensive care units/high risk patients; microbiological aspects; e) education programs.

Cross Infection↗

Hairy cell leukemia: preliminary results with alpha 2 (r) interferon.

Ten patients with hairy cell leukemia are being treated at our institution with a therapeutic schedule of alpha 2(r) interferon (2 X 10(6) IU/m2 s.c. three times per week). Five patients underwent splenectomy from 4 to 108 months before treatment; nonsplenectomized patients had spleens palpable 6 to 12 cm UCM. According to Quesada's response criteria, at the sixth month of therapy, one patient was considered a complete responder, 8 partial responders and one a minor responder, with no differences between splenectomized and nonsplenectomized patients. In nonsplenectomized patients the spleen returned to normal. Our data confirm that interferon, even at low dosages, is a very effective approach for hairy cell leukemia. No evidence was found to contraindicate such therapy.

Adult↗