Showing papers on "Interferon published in 1991"

Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism.

Abstract: Interferons have been shown to be potential anti-cancer agents and to inhibit tumor cell growth in culture. The in vivo mechanism of the anti-proliferative effect may be direct or indirect through the immune system; however, in vitro a primary mechanism of cytotoxicity is through the depletion of tryptophan. In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine. The inhibitory effect of interferon on many intracellular parasites such as Toxoplasma gondii and Chlamydia trachomatis is by the same mechanism. Elevated kynurenine levels have been found in humans in a number of diseases and after interferon treatment, and the enzyme is induced in rodents after administration of interferon inducers, or influenza virus. IDO induction also occurs in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process. The gene for IDO has been cloned and shown to be differentially regulated by IFN-alpha and IFN-gamma. IDO induction has been correlated with induction of GTP-cyclohydrolase, the key enzyme in pteridine biosynthesis. A direct role for IDO in pteridine synthesis has not been shown, and this parallel induction may reflect coordinate regulation of genes induced by IFN-gamma. A possible role for IDO in O2-radical scavenging and in inflammation is discussed.

The interferons. Mechanisms of action and clinical applications.

Abstract: The interferons (IFN) are one of the body's natural defensive responses to such foreign components as microbes, tumors, and antigens. The IFN response begins with the production of the IFN proteins (α, β, and γ), which then induce the antiviral, antimicrobial, antitumor, and immunomodulatory actions of IFN. Recent advances have led to Food and Drug Administration approval of five clinical indications for IFN. Interferon alfa is approved for hairy-cell leukemia, condyloma acuminatum, Kaposi's sarcoma in the acquired immunodeficiency syndrome, and non-A, non-B (type C) viral hepatitis. Interferon gamma has properties distinctive from those of IFNs α and β and is approved as an immunomodulatory treatment for chronic granulomatous disease. Promising clinical results with IFNs have also been reported for basal cell carcinoma, chronic myelogenous leukemia, cutaneous squamous cell carcinoma, early human immunodeficiency virus infection, hepatitis B, and laryngeal papillomatosis. Future clinical uses of IFNs may emphasize combination therapy with other cytokines, chemotherapy, radiation, surgery, hyperthermia, or hormones. (JAMA. 1991;266:1375-1383)

Interleukin 10 (IL-10) and Viral IL-10 Strongly Reduce Antigen-specific Human T Cell Proliferation by Diminishing the Antigen-presenting Capacity of Monocytes via Dowm'egulation of Class H Major Histocompatibility Complex Expression By Ren6 de Waal Malefyt, John Haanen, Hergen Spits,

Abstract: Summary Interleukin 10 (IL-10) and viral Ibl0 (v-IL-10) strongly reduced antigen-specific proliferation of human T cells and CD4 + T cell clones when monocytes were used as antigen-presenting cells. In contrast, IL-10 and v-Ibl0 did not affect the proliferative responses to antigens presented by autologous Epstein-Barr virus-lymphoblastoid cell line (EBV-LCL). Inhibition of antigen-specific T cell responses was associated with downregulation of constitutive, as well as interferon 3'or Ib4-induced, class II MHC expression on monocytes by IL-10 and v-Ibl0, resulting in the reduction in antigen-presenting of these ceUs. In contrast, IL-10 and v-Ibl0 had no effect on class II major histocompatibility complex (MHC) expression on EBV-LCL. The reduced antigenpresenting capacity of monocytes correlated with a decreased capacity to mobilize intracellular Ca 2 + in the responder T cell clones. The diminished antigen-presenting of monocytes were not due to inhibitory effects of II.-10 and v-Ibl0 on antigen processing, since the proliferative T cell responses to antigenic peptides, which did not require processing, were equaUy well inhibited. Furthermore, the inhibitory effects of Ibl0 and v-IL-10 on antigen-specific proliferative T cell responses could not be neutralized by exogenous Ib2 or Ib4. Although IL-10 and v-IL-10 suppressed IL-lc~, IL-1B, tumor necrosis factor ot (TNF-c~), and IL-6 production by monocytes, it was excluded that these cytokines played a role in antigen-specific T cell proliferation, since normal antigenspecific responses were observed in the presence of neutralizing anti-Ibl, -IL-6, and -TNF-tx mAbs. Furthermore, addition of saturating concentrations of IL-lot, IL-I~, IL-6, and TNF-o~ to the cultures had no effect on the reduced proliferative T cell responses in the presence of Ibl0, or v-Ibl0. Collectively, our data indicate that IL-10 and v-IL-10 can completely prevent antigen-specific T cell proliferation by inhibition of the antigen-presenting capacity of monocytes through downregulation of class II MHC antigens on monocytes.

Regulation of Trypanosoma cruzi infections in vitro and in vivo by transforming growth factor beta (TGF-beta).

Abstract: The effects of transforming growth factor beta (TGF-beta) on interferon gamma-mediated killing of the intracellular protozoan parasite Trypanosoma cruzi and on the course of T. cruzi infection in mice were investigated. Spleen cells from mice with acute T. cruzi infections were found to produce elevated levels of biologically active TGF-beta in vitro, and the possibility that TGF-beta may mediate certain aspects of T. cruzi infection was then addressed. When mouse peritoneal macrophages were treated with TGF-beta in vitro, the ability of IFN-gamma to activate intracellular inhibition of the parasite was blocked. This occurred whether cells were treated with TGF-beta either before or after IFN-gamma treatment. TGF-beta treatment also blocked the T. cruzi-inhibiting effects of IGN-gamma on human macrophages. Additionally, treatment of human macrophages with TGF-beta alone led to increased parasite replication in these cells. The effects of TGF-beta on T. cruzi infection in vivo were then investigated. Susceptible C57BL/6 mice developed higher parasitemias and died earlier when treated with TGF-beta during the course of infection. Resistant C57BL/6 x DBA/2 F1 mice treated with TGF-beta also had increased parasitemias, and 50% mortality, compared with no mortality in infected, saline-treated controls. A single dose of TGF-beta, given at the time of infection, was sufficient to significantly decrease resistance to infection in F1 mice and to exacerbate infection in susceptible C57BL/6 mice. Furthermore, a single injection of TGF-beta was sufficient to counter the in vivo protective effects of IFN-gamma. We conclude that TGF-beta, produced during acute T. cruzi infection in mice, is a potent inhibitor of the effects of macrophage activating cytokines in vivo and in vitro and may play a role in regulating infection.

High-frequency mutagenesis of human cells and characterization of a mutant unresponsive to both alpha and gamma interferons

Abstract: 2fTGH is a human cell line containing the selectable marker guanine phosphoribosyltransferase regulated by alpha interferon (IFN-alpha) Two IFN-alpha-unresponsive mutants were isolated previously at a low frequency (ca 10(-8)) by selecting mutagenized 2fTGH cells in selective medium containing 6-thioguanine and IFN-alpha By using five rounds of mutagenesis, mutants can be isolated at an appreciably higher frequency, greater than 3 x 10(-7) Five new mutants have been isolated, and all are recessive, as are the two mutants we described previously The seven mutants are in four complementation groups (U1-U4) Since several different types of mutants unresponsive to IFN-alpha have been isolated with high frequency, related approaches may succeed with other cytokines or growth factors Mutants in the two new complementation groups U3 and U4 are unresponsive to IFN-alpha and, surprisingly, also unresponsive to IFN-gamma They are also partially defective in response to double-stranded RNA These results indicate that the signaling pathways for the two types of IFN and double-stranded RNA share common components or that their function depends on common enzymes or transcription factors IFN receptors are unaffected in mutants U3A and U4A A major defect appears to be in the synthesis or activation of E, the transcription factor mediating the primary response to type I (alpha/beta) IFNs Band-shift complementation assays show that U3A contains the E gamma subunit but does not contain an active E alpha subunit after treatment with IFN-alpha

Recombinant Epstein-Barr virus with small RNA (EBER) genes deleted transforms lymphocytes and replicates in vitro

Abstract: Strains of Epstein-Barr virus (EBV) with deletions of the small RNA (EBER) genes were made by homologous recombination using the EBV P3HR-1 strain, which has undergone deletion of the essential transforming gene that encodes the EBV nuclear antigen, EBNA-2, and a DNA fragment that was wild type at the EBNA-2 locus but from which the EBER genes had been deleted. Even though the EBER and EBNA-2 genes are separated by 40 kilobases, selection for transforming P3HR-1 recombinants that required a restored EBNA-2 gene resulted in 20% cotransfer of the EBER deletion. EBER-deleted recombinants transformed primary B lymphocytes into lymphoblastoid cell lines (LCLs), which were indistinguishable form LCLs transformed by wild-type EBV in their proliferation, in latency-associated EBV gene expression, and in their permissiveness for EBV replication cycle gene expression. EBER-deleted virus from infected LCL clones could infect and growth-transform primary B lymphocytes. These procedures should be applicable to the construction of other EBV recombinants within 40 kilobases of the EBNA-2 gene. The EBER-deleted EBV recombinants should be useful in further evaluating the role of EBERs in EBV infection.

A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages.

Abstract: Murine peritoneal macrophages activated with interferon (IFN)-gamma and lipopolysaccharide (LPS) produce high levels of nitric oxide (NO) and are efficient in killing the intracellular protozoan parasites Leishmania major in vitro. Earlier studies have shown that NO, whose synthesis in murine macrophages is catalyzed by an inducible enzyme NO synthase, plays a major effector role in the host resistance against microbial infection. We now shown that both the NO synthesis and the leishmanicidal activity can be inhibited by prior treatment of the cells with recombinant interleukin 4 (IL4). IL4 treatment had no effect on the binding of IFN-gamma to macrophages but prevented the induction of NO synthase in these cells activated with IFN-gamma and LPS. Since IFN-gamma is produced by murine T helper type-1 (Th1) cells, whereas IL4 is secreted by Th2 cells, these results suggest a novel pathway by which Th2 cells regulate an activity of Th1 cells, namely by inhibiting the induction of NO synthase. These results may also account for the mechanism by which the disease-promoting Th2 cells counteract the host-protective effect of Th1 cells in leishmaniasis and other intracellular parasitic diseases.

Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function.

Abstract: The activation, proliferation, and antiviral properties of natural killer (NK) cells were examined in severe combined immunodeficiency (SCID) mice to determine the influence of mature T or B cells on virus-induced NK cell functions and to more conclusively determine the antiviral properties of prototypical CD3- NK cells. NK cells were activated to high levels of cytotoxicity 3 d after infection of mice with lymphocytic choriomeningitis virus (LCMV) or murine cytomegalovirus (MCMV). Analyses of spleen leukocytes from LCMV-infected mice by a variety of techniques indicated that the NK cells proliferated and increased in number during infection. Propidium iodide staining of the DNA of cycling cells revealed that the great majority of proliferating spleen leukocytes 3 d after LCMV infection was of the NK cell phenotype (CD3-, Ig-, Mac-1+, CZ1+, 50% Thy-1+), in contrast to uninfected mice, whose proliferating cells were predominantly of other lineages. Analyses of the NK cell responses over a 2 wk period in control CB17 mice infected with MCMV indicated a sharp rise in serum interferon (IFN) and spleen NK cell activity early (days 3-5) in infection, followed by sharp declines at later stages. In SCID mice the IFN levels continued to rise over a 10-d period, whereas the NK cell response peaked on day 3-5 and gradually tapered. In contrast to the immunocompetent CB17 mice, SCID mice did not clear the MCMV infection and eventually succumbed. SCID mice, again in contrast to immunocompetent CB17 mice, also failed to clear infections with LCMV and Pichinde virus (PV); these mice, infected as adults, did not die but instead developed long-term persistent infections. Depletion of the NK cells in vivo with antiserum to asialo GM1 rendered both SCID and CB17 control mice much more sensitive to MCMV infection, as shown by titers of virus in organs and by survival curves. In contrast, similar depletions of NK cells did not enhance the titers of the NK cell-resistant virus, LCMV. Two variants of PV, one sensitive to NK cells and the other selected for resistance to NK cells by in vivo passage, were also tested in NK cell-depleted SCID mice. The NK-sensitive PV replicated to higher titers in NK cell-depleted SCID mice, whereas the titers of the NK cell-resistant PV were the same, whether or not the mice had NK cells. These experiments support the concept that CD3- prototypical NK cells mediate resistance to NK cell-sensitive viruses via a mechanism independent of antiviral or "natural" antibody.(ABSTRACT TRUNCATED AT 400 WORDS)

Induction of interleukin-1 and -6 in human gingival fibroblast cultures stimulated with Bacteroides lipopolysaccharides.

Abstract: Normal human gingival fibroblasts stimulated in vitro by lipopolysaccharides (LPS) from oral Bacteroides species produced cell-free and cell-associated thymocyte-activating factors (TAF). Neutralization assays using antisera to human interleukin-1 alpha (HuIL-1 alpha), HuIL-1 beta, and HuIL-6 revealed that cell-free TAF was attributable mainly to IL-1 beta and that IL-6 augmented the TAF activity of IL-1 beta in the culture supernatant. Another factor(s), however, may also be involved in cell-free TAF. By contrast, the active entity of cell-associated TAF was ascribed to IL-1 alpha alone. Furthermore, IL-6 was detected mainly in the supernatant of fibroblast cultures stimulated with Bacteroides LPS. Fibroblasts pretreated with natural human beta or gamma interferon, but not those pretreated with alpha interferon, synthesized higher levels of cell-associated IL-1 alpha in response to stimulation by Bacteroides LPS; however, no interferons exhibited direct IL-1-inducing activity or synergistic IL-1-inducing activity with LPS. Endogenously induced beta interferon was suggested to be necessary for fibroblasts to produce cell-associated IL-1 alpha in response to Bacteroides LPS.

Interferon-induced and double-stranded RNA-activated enzymes: a specific protein kinase and 2',5'-oligoadenylate synthetases.

Abstract: Treatment of cells with interferon (IFN) results in the induction of two double-stranded RNA (dsRNA)-activated enzymes: a specific protein kinase and 2′-5′ linked oligoadenylate [pppA(2′p5′A)n referred to as 2-5A] synthetases. The protein kinase, when activated by dsRNA, becomes autophosphorylated and catalyzes and phosphorylation of the protein synthesis initiation factor, eIF2. The 2-5A synthetases, when activated by dsRNA, form 2-5A molecules capable of activating a latent endoribonuclease that degrades RNA. By inhibiting initiation of protein synthesis or by degrading of RNA, these enzymes play key roles in two independent pathways that regulate overall protein synthesis.

Expression of the terminal protein region of hepatitis B virus inhibits cellular responses to interferons alpha and gamma and double-stranded RNA.

Abstract: Constructs expressing the core, surface, X, or polymerase proteins of hepatitis B virus were transfected into human cells. In transient assays, only the polymerase inhibited the responses to interferons alpha and gamma (IFN-alpha and -gamma). Stable expression of the polymerase was achieved in the cell line 2fTGH, which carries an IFN-inducible marker gene, by growth under conditions that select for inhibition of the response to IFN-alpha, but the clones grew poorly. When expressed alone, the terminal protein domain of the polymerase gene inhibited the response to IFN-alpha and the reverse transcriptase plus RNase H domains appeared to be toxic. Clones of cells expressing terminal protein alone, selected for the loss of response to IFN-alpha, grew normally and had no detectable response to IFN-alpha, IFN-gamma, or double-stranded RNA. Binding of IFN-alpha to these cells was not impaired but did not lead to activation of the E alpha subunit of the IFN-induced transcription factor E. These observations are of potential importance in relation to the pathogenesis of chronic hepatitis B virus infection and the resistance of such infection to IFN-alpha therapy.

Isolation and characterization of a new mutant human cell line unresponsive to alpha and beta interferons.

Abstract: Previously we described human cell line 2fTGH, in which expression of guanine phosphoribosyltransferase is tightly controlled by the upstream region of interferon (IFN)-stimulated human gene 6-16. After mutagenesis of 2fTGH and selection with 6-thioguanine and IFN-alpha, we isolated 11.1, a recessive mutant that does not respond to IFN-alpha. We now describe U2, a second recessive mutant, selected similarly, that complements 11.1. U2 had no response to IFN-alpha or IFN-beta, and its response to IFN-gamma was partially defective. Although many genes did respond to IFN-gamma in U2, the 9-27 gene did not and the antiviral response of U2 cells to IFN-gamma was greatly reduced. Band shift assays showed that none of the transcription factors normally induced in 2fTGH cells by IFN-alpha (E and M) or IFN-gamma (G) were induced in U2. However, extracts of untreated U2 cells gave rise to a novel band that was increased by treatment with IFN-gamma but not IFN-alpha. Band shift complementation assays revealed that untreated and IFN-gamma-treated U2 cells lack the functional E gamma subunit of transcription factor E and that IFN-alpha-treated U2 cells do contain the functional E alpha subunit.

Inhibition of interferon-inducible gene expression by adenovirus E1A proteins: block in transcriptional complex formation.

Abstract: Infection with wild-type adenovirus 5, but not with a mutant lacking the E1A gene, prevented the induction by interferon (IFN) alpha of chloramphenicol acetyltransferase (CAT) activity in HeLaM cell lines that had been permanently transfected with chimeric CAT reporter genes driven by the transcriptional regulatory regions of the IFN-responsive genes 561 and 6-16. Similar inhibition of IFN-inducible CAT activity was observed in cells that were cotransfected with the same reporter genes and plasmids expressing either the E1A 289- or 243-amino acid protein. These proteins also prevented the induction of CAT activity by IFN-gamma from a cotransfected HLA-DR alpha-CAT gene. Experiments with E1A mutants mapped the inhibitory activity to amino acid residues 38-65 of these proteins. In a HeLa cell line permanently expressing the E1A 289-amino acid protein, the replication of vesicular stomatitis virus and encephalomyocarditis virus was not inhibited by IFN-alpha, suggesting a global blockade of IFN responses. In accord with this theory, induction of 561, 1-8, and (2'-5')oligoadenylate synthetase mRNAs by IFN was blocked in these cells at the transcriptional level. The observed transcriptional inhibition could be attributed to the lack of formation of the crucial IFN-stimulated gene factor 3 (ISGF3) transcriptional complex. As shown by mobility shift assays, this complex was not formed in the nuclear extracts of IFN-treated adenovirus-infected cells or IFN-treated E1A-producing cells. These nuclear extracts were deficient in both ISGF3 alpha and ISGF3 gamma subunits. However, they did not block the formation of ISGF3 complex from exogenously added components.

Severe cachexia in mice inoculated with interferon‐γ‐producing tumor cells

Abstract: Nude mice were inoculated with CHO/IFN-gamma cells, a line of Chinese hamster ovary tumor cells, that had been genetically engineered to produce murine IFN-gamma. Severe cachexia, as evident from body weight loss and reduced food intake, occurred in these mice, but not in those injected with CHO/control cells, i.e. the original, non-IFN-gamma-producing line. The essential role of IFN-gamma in the pathogenesis of cachexia was confirmed by the demonstration that monoclonal antibodies (MAbs) against IFN-gamma, given prior to injection of the tumor cells, prevented cachexia. In addition to IFN-gamma, the presence of the tumor cells was also required for cachexia to develop. As evident from pair-feeding experiments, reduced food intake could only partially account for the rapid and extensive body-weight loss. Cachexia was characterized by a marked reduction in the amount of interscapular fat tissue. Injected tumor cells exclusively invaded intraperitoneal adipose tissue and elicited an inflammatory cell infiltrate, indicating that interscapular fat loss was due to humoral factors. Our data suggest that, among the humoral factors responsible for cancer-associated cachexia, IFN-gamma plays a prominent role.

Immunocytochemical and virological characteristics of HIV-associated inflammatory myopathies: similarities with seronegative polymyositis.

Abstract: We performed an immunoperoxidase study on muscle biopsy specimens from 19 patients with polymyositis who were seropositive for human immunodeficiency virus (HIV) (21 specimens) and 5 HIV-seronegative patients with polymyositis and compared the findings. A quantitative analysis of T cells and T-cell subsets, B cells, natural killer cells, interleukin-2 receptor-positive cells, and macrophages was performed on serial sections from all the specimens. Localization of major histocompatibility complex (MHC)-I and -II antigens, alpha and gamma interferon, and HIV antigens (p24, gp120, and gp41) was performed using specific antisera. In specimens from HIV-positive and seronegative patients, the predominant cell population was CD8+ cells and macrophages invading or surrounding healthy muscle fibers that expressed MHC-I antigen on their surface. The endomysial infiltrates in specimens from HIV-positive patients differed from those seen in specimens from the seronegative patients only by a significant reduction of the CD4+ cells (12.6 +/- 3.2% versus 21.1 +/- 4.2%). HIV antigens were seen in occasional interstitial mononuclear cells (but not in muscle fibers) in 6 of the 21 specimens from HIV-positive patients. Interferon was not localized. We conclude that the development of HIV-associated polymyositis does not appear to be related to direct infection of the muscle fibers by HIV but rather is due to a T-cell-mediated and MHC-I-restricted cytotoxic process, perhaps triggered by HIV. Because this immunopathological mechanism is common in both HIV-associated polymyositis and polymyositis alone, it is suggested that viruses may also be responsible in triggering polymyositis.

Interferon-regulated Mx genes are not responsive to interleukin-1, tumor necrosis factor, and other cytokines.

Abstract: Accumulation of Mx gene products in cells of patients and experimental animals has been recognized as a useful marker for detecting minute quantities of biologically active interferon (IFN). Goetschy et al. (J. Goetschy, H. Zeller, J. Content, and M. A. Horisberger, J. Virol. 63:2616-2622, 1989) reported that not only IFNs but also interleukin-1 (IL-1) and tumor necrosis factor (TNF) were potent inducers of the human Mx genes. However, we observed no Mx induction in cultured human fibroblasts or in human peripheral blood mononuclear cells treated with various concentrations of IL-1 alpha or TNF-alpha. Mx induction was found in the spleens of mice treated with TNF-alpha or IL-1 alpha, but this effect could be neutralized with antibodies to murine IFN-alpha/beta. Of the other cytokines that we tested (IL-2, IL-6, and granulocyte-macrophage colony-stimulating factor), only IL-2 induced the Mx genes in peripheral blood mononuclear cells, but antibodies to human IFN-beta efficiently neutralized this effect. Our results thus indicate that IFNs are the only cytokines with intrinsic Mx-inducing activity.

Inhibition of the cellular response to interferons by products of the adenovirus type 5 E1A oncogene.

Abstract: Expression of the E1A oncogene of adenovirus type 5 inhibits the response of interferon (IFN)-inducible constructs to Type I (alpha,beta) and II (gamma) IFNs in transient transfection assays. In human cell lines stably expressing E1A mRNA and protein acquisition of an antiviral state and the induction of a number of genes in response to alpha- and gamma-IFNs is inhibited. A short IFN-stimulable response element (ISRE) present in the 5' flanking region of a number of genes mediates induction by alpha- and gamma-IFNs. In cells expressing E1A there is a substantial reduction in the levels of the ISRE-binding factors E and M, inducible by alpha-IFN, and of factor G, inducible by gamma-IFN. In E1A-expressing cells the E alpha subunit of factor E is activated normally in response to alpha-IFN; the defect is in the production or activation of the E gamma subunit. The inhibitory activity of E1A is lost upon deletion of the CR1 domain. The induction of HLA class II genes by gamma-IFN, which involves a different DNA response element(s), and of beta-IFN mRNA in response to double-stranded RNA are also inhibited by E1A. An essential component(s) of a number of signalling pathways must, therefore, be subject, directly or indirectly, to inhibition by E1A.

Endogenously produced interferon α protects mice from herpes simplex virus type 1 corneal disease

Abstract: Intravenous (i.v.) injection of u.v. light-inactivated herpes simplex virus type 1 (UV HSV-1) at the time of HSV-1 corneal infection reduced the cytotoxic T lymphocyte (CTL) response to HSV-1, and significantly reduced the incidence of HSV-1-induced corneal stromal disease in A/J mice. The spread of HSV-1 through the eye after corneal infection, detected using engineered HSV-1 (US3::Tn5-lacZ) with the lacZ gene under the transcriptional control of the viral late gene promoter for glycoprotein C, was also markedly reduced by i.v. UV HSV-1 injection. The restriction of HSV-1 corneal invasiveness in i.v. UV HSV-1-injected mice preceded the onset of a detectable specific cell-mediated or humoral immune response to HSV-1, and was accompanied by an elevated serum titre of interferon (IFN-α), reversed by anti-IFN-α/β antibody, and mimicked by systemic IFN-α treatment. IFN-α-treated mice developed a normal CTL response to HSV-1 after corneal infection, but the corneal invasiveness of the virus was markedly reduced and none of the treated mice developed corneal stromal disease. Together with our previous findings that HSV-1-specific CTLs participate in the pathogenesis of corneal stromal disease, these results indicate that i.v. injection of UV HSV-1 at the time of corneal infection may prevent stromal disease by the combined effects of IFN-mediated reduction of the spread of virus in the cornea and inhibition of the activity of the HSV-specific T lymphocytes that induce tissue destruction in the corneal stroma.

Cytokine-induced enhancement of ICAM-1 expression results in increased vulnerability of tumor cells to monocyte-mediated lysis.

Abstract: Pretreatment of the human melanoma cell line, A375, and the human colon carcinoma cell line, HT-29, with certain cytokines was found to increase the vulnerability of these cells to monocyte-mediated killing. This activity was found to correlate with increased expression of intercellular adhesion molecule-1 (ICAM-1) on the tumor cells and was blocked by anti-ICAM-1 antibodies. Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. IFN-alpha and IL-1 beta, however, induced only small increases in ICAM-1 expression and enhanced the lysis of the A375 cells but not the HT-29 cells by monocytes. These differences may be the result of a higher basal expression of ICAM-1 found on the A375 cells when compared with the HT-29 cells. These data indicate that regulation of ICAM-1 expression on tumor cells can alter the vulnerability of these cells to lysis by monocytes.