MHC class II antigens on the epithelial cells of the human gastrointestinal tract.
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Gastric Mucosa↗
Biomedical subjects
M R Capobianchi
Publications and source records attributed to M R Capobianchi.
In vitro selection of human immunodeficiency virus type 1 resistant to 3'-azido-3'-deoxythymidine.
3'-Azido-3'-deoxythymidine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) was obtained by growing HTLV-IIIB in C8166 cell cultures in the presence of inhibitory concentrations of AZT. The AZT-resistant HIV-1 was capable of replicating, as measured by infectious virus yield, and inducing cytopathic effect in the presence of AZT concentrations able to completely suppress the replication of parental HTLV-IIIB. Cloning of the AZT-resistant HIV-1 revealed that a number of different variants of HIV-1 with various degrees of sensitivity to AZT emerged during propagation of HTLV-IIIB in C8166 cells in the presence of the drug. PCR experiments performed on DNA extracted from C8166 cells infected with a resistant strain revealed that viral DNA was produced in the presence of inhibitory concentrations of AZT, while viral DNA in C8166 cells infected with the parental virus was drastically inhibited. Reverse transcriptase isolated from the AZT-resistant HIV-1 variant failed to show resistance to AZT 5'-triphosphate.
Antiviral Agents↗
Recombinant glycoprotein 120 of human immunodeficiency virus is a potent interferon inducer.
Cells infected with human immunodeficiency virus (HIV) induce antiviral activity in peripheral blood mononuclear cells (PBMC) from healthy donors. This activity is neutralized by anti-interferon-alpha antibody and partially destroyed at pH 2. Previous studies with enriched cell populations and monoclonal antibodies suggest that B lymphocytes are the main IFN-producing cells, and that both CD4 and HLA class II antigens are essential for IFN induction. Since the initial event of HIV infection of CD4+ cells is the interaction of the virus coat glycoprotein gp120 with CD4 molecule, we investigated whether gp120 is responsible for IFN induction. Using PBMC and recombinant gp120 obtained from a baculovirus expression system, dose-dependent induction of antiviral activity was observed with titers approaching 10(3) IU/ml. This induction was blocked in the presence of antibody to gp120. The antiviral activity was characterized as IFN-alpha by neutralization with IFN alpha-specific antibody. Preincubation of PBMC with anti-CD4 or the presence of soluble CD4 during incubation inhibited IFN induction, indicating that interaction of gp120 with cell-associated CD4 is responsible for this induction. Neither lymphoproliferation nor interleukin-2 (IL-2) production was observed during IFN induction. However, class G immunoglobulin secretion was enhanced by gp120, indicating that B cells are direct or indirect targets of gp120 stimulation in this experimental system. Since gp120 is shed from HIV-infected cells and occurs in the serum of acquired immunodeficiency syndrome (AIDS) patients, our data suggest that this glycoprotein is responsible for the induction of endogenous IFN and the polyclonal activation of B cells both of which are observed in AIDS patients.
B-Lymphocytes↗
Acid lability is not an intrinsic property of interferon-alpha induced by HIV-infected cells.
Human immunodeficiency virus (HIV)-infected cells induce acid-labile interferon-alpha (al-IFN-alpha) in cultures of mononuclear cells from peripheral human blood. We have investigated the physiochemical properties of such preparations to elucidate the reasons for acid-lability of this IFN. Al-IFN-alpha is a mixture of both glycosylated and unglycosylated molecules as shown by separation on Concanavalin-A Sepharose. Acid-lability is associated only with glycosylated molecules. Upon chromatography of the glycosylated fraction on Sepharose coupled to IFN-alpha-specific antibody, the portion of the IFN that is retained and eluted with guanidine-HCl is acid-stable, whereas the excluded antiviral activity is acid-labile, and is partially neutralized by antibodies to either IFN-alpha or IFN-gamma. Also, upon further purification of the unglycosylated fraction on the same antibody column, all antiviral activity remains indistinguishable from conventional IFN-alpha. Reconstitution experiments showed that glycosylated material excluded from the anti-IFN-alpha column potentiates antiviral activity of the IFN that is specifically retained by the column. This potentiation is abolished by acid treatment. Similar results are obtained with al-IFN-alpha from the serum of acquired immunodeficiency syndrome (AIDS) patients, indicating that its acid-lability is also the consequence of an acid-labile component that is capable of enhancing the antiviral activity. The potentiation of antiviral activity obtained by combining recombinant preparations of IFN-alpha and IFN-gamma suggests that the cooperating molecule is IFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
Acids↗
Absence of circulating interferon in patients with inflammatory bowel disease. Suggestion against an autoimmune etiology.
Whether inflammatory bowel diseases (IBD) can be classified as autoimmune disorders is not established. Since circulating acid-labile interferon-alpha (IFN-alpha) is believed to reflect autoimmune reactions, we tested sera from two groups of IBD patients for the presence of circulating IFN. No detectable IFN was found in 51 serum samples of IBD patients. Furthermore, in no serum sample of IBD patients were neutralizing anti-IFN antibodies found. In contrast, acid-labile IFN-alpha was present in sera from 21/52 HIV-infected and from 6/14 systemic lupus erythematosus patients. These observations provide evidence that IBD differs from systemic autoimmune disorders, at least for the presence of circulating IFN.
Autoantibodies↗
Evidence against an autoimmune aetiology for inflammatory bowel diseases.
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Autoimmune Diseases↗
Interferon-alpha (IFN-alpha) production by human intestinal mononuclear cells. Response to virus in control subjects and in Crohn's disease.
The virus induced production of interferon alpha by human intestinal lamina propria mononuclear cells was investigated. Intestinal and autologous peripheral cells from control subjects and patients with Crohn's disease were cultured in vitro with and without stimulation with the Newcastle disease virus. Interferon alpha was measured and characterised in the culture supernatants after 12 hours and the kinetics of production was evaluated over the following four days of culture. No detectable interferon alpha was found in cultures of unstimulated intestinal and autologous peripheral mononuclear cells from controls and Crohn's disease whereas interferon alpha was released in all cultures stimulated with the virus. In all 12 hours experiments in both groups, virus stimulated intestinal mononuclear cells yielded significantly less interferon alpha than the autologous peripheral cells. The kinetics experiments showed that control intestinal mononuclear cells appeared to be poorly responsive to virus stimulation showing a release of interferon alpha significantly lower than that of the autologous peripheral cells. The interferon alpha release at day 4 by control cells (either intestinal or peripheral) did not differ from that measured after the first 12 hours. In contrast, the interferon alpha produced by Crohn's disease cells progressively increased during the culture period and the amount of interferon alpha measured at day 4 was significantly higher than that released at 12 hours. These data suggest that normal human intestinal mononuclear cells are down regulated in their capability of producing interferon alpha and that in Crohn's disease their activation for this function is enhanced. These data also suggest that in Crohn's disease intestinal mononuclear cells exhibit a transient hyporesponsiveness to in vitro stimulation possibly related to massive in vivo exposure to interferon alpha inducers.
Cells, Cultured↗
Cytotoxic activity of intestinal lamina propria lymphocytes on human immunodeficiency virus (HIV)-infected cells.
The phenotype and cytotoxic activity of lamina propria lymphocytes (LPL) from the colorectal mucosa have been investigated primarily to analyse the role of LPL in human immunodeficiency virus (HIV) infection. The results reported here show that LPL strictly required a proliferative stimulus [either interleukin-2 (IL-2) or phytohaemaglutinin (PHA) to develop strong in vitro cytotoxicity, since freshly isolated LPL do not exhert cytotoxicity against either natural killer (NK)-sensitive or NK-resistant target cells. The cytotoxicity of activated LPL against a large panel of myeloid tumours or colorectal carcinoma target cells shows the irrelevance of the tissue origin of target cells. Moreover, activated LPL lysed HIV-infected H9 cells more efficiently than peripheral blood lymphocytes (PBL), and were susceptible to HIV infection. In contrast, unstimulated LPL failed to be cytotoxic and susceptible to HIV. Thus, we strongly suggest that for the lymphocytes of the colorectal mucosa expression of cytotoxic activity and susceptibility to HIV-infection show two faces of the same coin, and therefore may be relevant in understanding the mechanisms and paths of transmission of HIV infection.
Cells, Cultured↗
Role of interferon in lethality and lymphoid atrophy induced by Coxsackievirus B3 infection in mice.
To assess the importance of interferon (IFN) in the pathology of coxsackievirus B3 (CVB-3) infection, we evaluated both mortality rate and lymphoid involution in young adult BALB/C mice infected with lethal doses of the virus and treated either with anti-IFN antibody or with murine IFN-alpha/beta. Administration of antibody to IFN caused a profound worsening of the pathology and an increase in the mortality rate in infected animals. Treatment with murine IFN exerted a significant ameliorative effect on lethality when administered concomitantly with or soon after virus infection. The extent of this protection was correlated with the plasma levels of exogenous or endogenous IFN at 6 h postinfection, whereas no correlation with IFN titers was found later. The effects of IFN apparently were not directly mediated by antiviral effects, because at the times studied, no relation was found between IFN levels and virus titers, at least in the plasma of the infected animals. Lymphoid atrophy, assessed by measuring spleen weight, was only partially reversed by early IFN treatment. These data suggest that IFN production is critical during the early phases of infection, whereas it does not seem to play a significant protective role at later stages.
Animals↗
Alterations of T-cell functions during Friend leukemia complex infection: defective signal transduction?
Proliferative and interleukin responses to T-cell mitogens such as concanavalin A (Con A) were rapidly and progressively reduced in BALB/c mice infected with the Friend leukemia complex (FLC) or its helper, Friend murine leukemia virus (F-MuLV). In contrast, a combination of the protein kinase C activator phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and the Ca++ ionophore A23187 elicited a normal lymphoproliferative response up to 8 days postinfection (p.i.) and normal interleukin-2 (IL-2) and interferon-gamma responses up to day 14 p.i. Exogenous IL-2 failed to restore the lymphoproliferative response of infected cells regardless of the stimulation used. These results showed that the T-cell deficits may be at least partly attributable to a derangement of the signal transduction pathway leading to activation. Spleen cells passed through nylon wool columns reacquired a normal responsiveness to Con A +/- TPA up to 14 days p.i. The latter finding suggests that the alterations in signal transduction are not caused by primary defect of the responder-T cells but may result from an extrinsic suppressive mechanism.
Animals↗
Spontaneous release of interferon gamma by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon gamma inducers.
The spontaneous induced release of interferon gamma (IFN gamma) by cultured intestinal lamina propria lymphocytes was investigated in patients with Crohn's disease. In contrast to normal lymphocytes, intestinal lymphocytes from these patients spontaneously released IFN gamma and seemed to contain IFN gamma in their cytoplasm. Autologous peripheral lymphocytes did not release IFN gamma. When stimulated with interferon inducers lamina propria lymphocytes from Crohn's disease tissue showed an increase in IFN gamma release 24 hours after induction with no appreciable further increase over the next two days of culture, while in control cells, either peripheral or intestinal, IFN gamma release progressively increased, peaking 72 hours after induction. These findings indicate that in Crohn's disease the intestinal lymphocytes are stimulated in vivo to produce IFN gamma and that the spontaneous IFN gamma production is compartmentalised to the gut lymphocytes. These data support the concept that locally released IFN gamma has a crucial role in cell interactions in the lamina propria and contribute to the locally occurring immune phenomena in Crohn's disease, including the increased epithelial expression of major histocompatibility complex class II antigens.
Cell Membrane↗
Selective deficiency of interferon-gamma production in the hyper-IgE syndrome. Relationship to in vitro IgE synthesis.
We measured the in vitro production of interferon-gamma (IFN-gamma) in five cases of hyper-IgE syndrome (HIgE), induced by mitogens, calcium ionophores and phorbol ester. The biosynthesis of IFN-gamma was severely reduced or undetectable in HIgE, while it was near normal in most atopic patients. The in vitro spontaneous production of IgE was increased overall in HIgE patients, although no correlation was found with serum IgE levels. Recombinant interleukin-4 (IL-4) induced a further increase in IgE synthesis, and its effect was totally antagonized by recombinant IFN-gamma; the same pattern of response was also observed in atopic subjects with high production of IgE. IFN-alpha synergized with IL-4 on IgE synthesis, whereas recombinant IL-6 gave opposite changes in individual cases tested. We propose that IFN-gamma deficiency may be responsible for some of the features of HIgE patients, including IgE levels and infections.
Adolescent↗
The biological basis for clinical use of interferon.
Interferons represent the body's most rapid defence against virus infection. Natural recovery from viral infections is correlated with interferon production; the inhibition of interferon enhances the severity of infection and interferon has been shown to protect animals from some viral infections. beta-Interferon is produced by fibroblasts in response to viral infection. Leucocyte (a) interferon may be induced by foreign or infected cells or by viruses, and it is continuously released into the bloodstream during infection, declining with time. gamma-Interferon are produced later in viral infection by virus-sensitized T lymphocytes. The antiviral action of interferon is induced by interaction with specific receptors on cell surfaces leading to translation of antiviral proteins. Interferons may also enhance immune responses by increasing expression of lymphocyte surface antigens and by increasing the cytotoxic activity of natural killer cells. In chronic hepatitis B and C, it seems likely that interferon's antiviral activity is responsible for the early fall of viral products, while its immunomodulatory activity is responsible for long-term effects, including the destruction of infected hepatocytes, with persistent loss of viral antigens and seroconversion.
Hepatitis, Viral, Human↗
Biological activity of gamma interferon.
Gamma interferon (IFN) is mainly produced, under natural conditions, by antigen-specific T lymphocytes during the immune response. Cooperation with macrophages is required. Although discovered in 1965 as an antiviral agents, today this type of IFN is considered a lymphokine deeply involved in the regulation of several immunological reactions such as: cytotoxicity; expression of surface antigens, mainly MHC antigens; cellular differentiation; antibody production; macrophage activation. In this review the authors discuss some aspects of the biology of gamma IFN as pleiotropic lymphokine as well as the cellular events leading to gamma IFN production.
Animals↗
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↗
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↗
Replication of human immunodeficiency virus: yield of infectious virus under single growth cycle conditions.
Replication kinetics of HIV was studied under single growth cycle conditions by backtitrating infectious virus released or remained cell-associated at each time point. Under these conditions HIV seems to replicate faster than previously estimated. The amount of cell-associated virus always exceeds the one detectable in the medium.
Cells, Cultured↗