Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The success of cancer gene therapy is likely to require the targeting of multiple antitumor mechanisms. One strategy involves the use of attenuated, replication-competent virus vectors, such as herpes simplex virus type 1 (HSV-1) mutant G207, which is able to replicate in human tumor cells with resultant cell death and tumor growth inhibition, yet is nonpathogenic in normal tissue. In this study, we demonstrate that infection of established tumors with G207 also induces a highly specific systemic anti-tumor immune response. In a syngeneic, bilateral established subcutaneous tumor model, with mouse CT26 colorectal carcinoma cells in BALB/c mice or M3 melanoma cells in DBA/2 mice, unilateral intratumoral inoculation with G207 caused a significant reduction in the growth of both the inoculated and contralateral noninoculated tumors. This elicited anti-tumor response is dependent on viral infection of the tumor, as intradermal inoculation of G207 in BALB/c mice had no effect on CT26 tumor growth. Treatment of subcutaneous CT26 tumors by intratumoral inoculation of G207 induced a tumor-specific T cell response. CD8+ cytotoxic T lymphocyte (CTL) activity was generated that recognized a dominant "tumor-specific" major histocompatibility complex (MHC) class I-restricted epitope (AH1) from CT26 cells. In immune-competent animals, G207 is acting as an in situ tumor vaccine. Therefore, intratumoral G207 inoculation is able to inhibit tumor growth both by local cytotoxic viral replication in tumor cells and induction of a systemic anti-tumor immune response.
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PMID:Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. 1004 91

Oromucosal administration of murine interferon-alpha/beta (IFN-alpha/beta) or individual recombinant species of murine IFN-alpha, IFN-beta, or IFN-gamma or recombinant human IFN-alpha1-8, which is active in the mouse, exerted a marked antiviral activity in mice challenged systemically with a lethal dose of encephalomyocarditis virus (EMCV), vesicular stomatitis virus (VSV), or varicella zoster virus (VZV). The effects observed were dose dependent and similar in magnitude to those observed following parenteral administration of the same dose of IFN. No antiviral activity was observed after oromucosal administration of murine IFN-alpha/beta in animals in which the IFN receptor had been inactivated by homologous recombination. In contrast to parenteral treatment, oromucosal IFN therapy was found to be ineffective when IFNs were administered before virus infection. Oromucosal administration of IFN-alpha also exerted a marked antitumor activity in mice injected i.v. with highly malignant Friend erythroleukemia cells or other transplantable tumors, such as L1210 leukemia, which has no known viral etiology, the EL4 tumor, or the highly metastatic B16 melanoma. These results show that high doses of IFN can be administered by the oromucosal route apparently without ill effect, raising the possibility that the oromucosal route will prove to be an effective means of administering high doses of IFN that are clinically effective but poorly tolerated.
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PMID:Oromucosal interferon therapy: marked antiviral and antitumor activity. 1009 Apr

The proteasome, an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells, is responsible for the degradation of most cellular proteins and is believed to be the main source of MHC class I-restricted antigenic peptides for presentation to CTL. Inhibition of the proteasome by lactacystin or various peptide aldehydes can result in defective Ag presentation, and the pivotal role of the proteasome in Ag processing has become generally accepted. However, recent reports have challenged this observation. Here we examine the processing requirements of two HLA A*0201-restricted epitopes from HIV-1 reverse transcriptase and find that they are produced by different degradation pathways. Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7. In contrast, both lactacystin treatment and expression of LMP7 induce the presentation of the N-terminal VIYQYMDDL epitope. Consistent with these observations we show that up-regulation of LMP7 by IFN-gamma enhances presentation of the VIYQYMDDL epitope. Hence interplay between constitutive and IFN-gamma-inducible beta-subunits of the proteasome can qualitatively influence Ag presentation. These observations may have relevance to the patterns of immunodominance during the natural course of viral infection.
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PMID:IFN-gamma exposes a cryptic cytotoxic T lymphocyte epitope in HIV-1 reverse transcriptase. 1035 50

Ag-specific CTL can protect against tumors and some viral infections and may be useful for adoptive immunotherapy. Here, we show that purified CD8+ T cells from naive C57BL/6 mice can be primed in vitro with different immunogenic peptides, which bind to MHC class I gene products, and IL-2 to exhibit specific and MHC-restricted effector function in vitro and in vivo protection against lymphocytic choriomeningitis virus infection and B16.F10 melanoma lung metastases. Limiting dilution assays in the absence of feeder cells with highly purified CD8+ T cells from two transgenic mice strains, each expressing a different MHC class I-restricted TCR, indicated that only peptide and IL-2, but not TCR- cells, were required for the growth of naive CD8+ T cells. These alternative minimal requirements for the activation and expansion of specific CD8+ T lymphocytes, without the need for professional APC, may be exploited for adoptive immunotherapy.
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PMID:Protective immunity from naive CD8+ T cells activated in vitro with MHC class I binding immunogenic peptides and IL-2 in the absence of specialized APCs. 1038 32

The etiologic hantavirus of the 1993 emergence of an acute pulmonary failure syndrome in the area around northwestern New Mexico was quickly recognized as related to the Hantaan virus responsible for the outbreak of Korean epidemic hemorrhagic fever (EHF) among UN troops in 1951. Discovery of the new disease which was named the hantavirus pulmonary syndrome (HPS) and its causative agent the Sine Nombre virus (SNV) inspired detailed comparisons between the two disorders. Major damage to the epithelial cells of the capillaries and arterioles throughout the body leading to extensive capillary leak and subsequent hypotension and shock was the common denominator. The lung capillaries and arterioles were the focus of attack that could lead to rapid pulmonary failure in HPS and the corresponding renal and retroperitoneal vessels that caused a more protracted illness in EHF, but both displayed remarkably similar peripheral blood abnormalities including abnormal mononuclear cells, immature neutrophilia, thrombocytopenia, and hemoconcentration characteristic enough to make blood smear examination a useful tool in early diagnosis. There are evidences that a heavy virus presence in the involved endothelial cells is accompanied by various mononuclear cells capable of generating potent immune response in these areas. Relevant toxic effects of systemically-administered high-dose interleukin-2 for resistant cancers include fever, chills, diarrhea, renal dysfunction, capillary leak syndrome accompanied by hypotension requiring aggressive pressor support, and occasional pleural effusions with diffuse pulmonary infiltrates and hypoxia severe enough to require ventilatory assistance. Peripheral blood mononuclear cells cultured in vitro with IL-2 secrete secondary cytokines such as IL-1, TNF-alpha, and interferon-gamma (IFN-gamma). TNF-alpha, implicated in the pathophysiology of septic shock, is capable of inducing adult respiratory distress syndrome (ARDS) in experimental animals and humans. The strong similarity of these effects to the manifestations noted in the hantavirus diseases justifies the conviction that these and other cytokines involved in potent immune responses would constitute the pathogenic toxic substances predicted by perceptive early investigators of EHF. This concept is favored by clear indications that in both diseases active virus infection disappears the first few days and the ages of involvement correlate with periods of immunocompetence. The paradox of systemic injections of IL-2 that risk hantavirus-type toxicities for treating renal cell carcinoma and melanoma might be avoided by giving potentially more efficacious plant mitogens like PHA as previously reported. The expanded disclosure of a collaborator's method suggesting superior potential for cancer cure involves a unique application of pokeweed mitogen that delivers various cellular and cytokine responses directly to the tumor.
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PMID:Implications of the analogy between recombinant cytokine toxicities and manifestations of hantavirus infections. 1085 Mar 56

Human CMV (HCMV) retinitis frequently leads to blindness in iatrogenically immunosuppressed patients and in the end stage of AIDS. Despite the general proinflammatory potential of HCMV, virus infection is associated with a rather mild cellular inflammatory response in the retina. To investigate this phenomenon, the influence of HCMV (strains AD169 or Hi91) infection on C-X-C chemokine secretion, ICAM-1 expression, and neutrophil recruitment in cultured human retinal pigment epithelial (RPE) cells was studied. Supernatants from infected cultures contained enhanced levels of IL-8 and melanoma growth-stimulating activity/Gro alpha and induced neutrophil chemotaxis compared with supernatants from uninfected RPE cells. Despite HCMV-induced ICAM-1 expression on RPE cells, binding of activated neutrophils to HCMV-infected RPE cells and subsequent transepithelial penetration were significantly reduced. Reduced neutrophil adhesion to infected RPE cells correlated with HCMV-induced up-regulation of constitutive Fas ligand (FasL) expression. Functional blocking of FasL on RPE cells with the neutralizing mAbs NOK-1 and NOK-2 or of the Fas receptor on neutrophils with mAbB-D29 prevented the HCMV-induced impairment of neutrophil/RPE interactions. Fas-FasL-dependent impairment of neutrophil binding had occurred by 10 min after neutrophil/RPE coculture without apoptotic signs. Neutrophil apoptosis was first detected after 4 h. Treatment of neutrophils with a specific inhibitor of caspase-8 suppressed apoptosis, whereas it did not prevent impaired neutrophil binding to infected RPE. The current results suggest a novel role for FasL in the RPE regulation of neutrophil binding. This may be an important feature of virus escape mechanisms and for sustaining the immune-privileged character of the retina during HCMV ocular infection.
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PMID:Decreased neutrophil adhesion to human cytomegalovirus-infected retinal pigment epithelial cells is mediated by virus-induced up-regulation of Fas ligand independent of neutrophil apoptosis. 1103 78

Antigen-specific CD8-expressing T cells play a crucial role in the host's defense against viral disease and malignancy. Epitope-specific CD8(+)T cell responses to malignant and viral disease can be accurately measured using tetramers (tHLA) of HLA class I molecules loaded with antigenic peptides. In addition, tHLA have been used to evaluate immune responses to antigen-specific immunization. tHLA bind specifically to complementary T-cell receptor (TCR) structures on the surface of T cells expressing the CD8 coreceptor. Surprisingly, however, CD8(-) cells binding tHLA are often observed. This study uses four-color flow cytometry to show that HLA-A*0201-tHLA-stained CD8(-) cells can be divided into two subsets: 87% represent B-lymphocytes (CD19(+), CD45RA(+), HLA-DR(+), and CD20(+)), and 13% represent T-helper cells (CD3(+), CD4(+), CD45RA(+), and CD27(+)). This phenomenon is not HLA-restricted because it could be observed even in peripheral blood mononuclear cells (PBMC) from a non HLA-A*0201-expressing healthy donor. In addition, no T-cell receptor was detected on the B-lymphocytes. Retrospective enumeration of vaccine-induced CD8(-) tHLA cells in 243 PBMC samples from 36 patients with melanoma undergoing peptide vaccination revealed that tHLA staining is not dependent on immunization status or the presence of CD8(+) tHLA(+) T cells. These findings, suggest that the nonspecific binding of tHLA to non-TCR-expressing T cells requires a careful interpretation of results and further steps in preparation of sample for tHLA-based sorting of epitope specific T cells.
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PMID:Characterization of CD8(-) HLA class I/epitope tetrameric complexes binding T cells. 1221 75

Varicella-zoster virus glycoprotein E (gE) is the most abundant VZV glycoprotein on the surface of virus-infected cells. VZV gE has targeting sequences for the trans-Golgi network (TGN) and is transported from the ER to the TGN in infected and gE-transfected cells. In this study, VZV gE expressing melanoma cell lines were generated. gE is expressed under the control of the reverse Tet repressor (Tet-On). gE induced by Tet-On is retained at the ER as well as in the cis Golgi by immunofluorescence confocal microscopy. To test whether other viral protein(s) may facilitate gE trafficking and surface localization, MSPgE-vOka virus that contains MSPgE in place of wt gE was made. MAb 3B3 anti-gE does not bind to MSPgE. This MAb was used to track the localization of gE in Met-gE cells post MSPgE-vOka infection. gE became detectable mostly at the TGN and on the cell surface after viral infection. These data indicate that viral proteins facilitate the trafficking and cell surface expression of gE.
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PMID:Varicella-zoster virus infection facilitates VZV glycoprotein E trafficking to the membrane surface of melanoma cells. 1262 89

The search for new pharmaceuticals that are specific for diseased rather than normal cells in the case of cancer and viral disease has raised interest in locally acting drugs that act over short distances within the cell and for which different cell compartments have distinct sensitivities. Thus, photosensitizers (PSs) used in anti-cancer therapy should ideally be transported to the most sensitive subcellular compartments in order for their action to be most pronounced. Here we describe the design, production, and characterization of the effects of bacterially expressed modular recombinant transporters for PSs comprising 1) alpha-melanocyte-stimulating hormone as an internalizable, cell-specific ligand; 2) an optimized nuclear localization sequence of the SV40 large T-antigen; 3) an Escherichia coli hemoglobin-like protein as a carrier; and 4) an endosomolytic amphipathic polypeptide, the translocation domain of diphtheria toxin. These modular transporters delivered PSs into the nuclei, the most vulnerable sites for the action of PSs, of murine melanoma cells, but not non-MSH receptor-overexpressing cells, to result in cytotoxic effects several orders of magnitude greater than those of nonmodified PSs. The modular fusion proteins described here for the first time, capable of cell-specific targeting to particular subcellular compartments to increase drug efficacy, represent new pharmaceuticals with general application.
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PMID:Recombinant modular transporters for cell-specific nuclear delivery of locally acting drugs enhance photosensitizer activity. 1269 81

An impediment encountered in many viral-based gene therapy clinical trials has been the rapid destruction of the transgene by the host's immune response. The processing and presentation of antigens through the class I major histocompatibility complex (MHC) pathway is the initial specific response to viral infection. Disruption of the class I MHC pathway by herpes simplex virus (HSV) or the human cytomegalovirus (HCMV) results in a decrease of the CD8(+) cytotoxic T lymphocyte (CTL) response and prolongs survival of infected cells in the host. Two viral immune suppression genes that interfere with the class I MHC presentation pathway, the HSV type I ICP47 gene and HCMV US11 gene, were cloned and each incorporated into a retroviral vector. HSV ICP47 and HCMV US11 transgenes were expressed in multiple cells lines and compared for their abilities to reduce antigen presentation on the cell surface by class I MHC. Retroviral supernatants were used to transduce human, canine, and rat cell lines. Fluorescence-activated cell sorter (FACS) analysis of US11- and ICP47-transduced cell lines demonstrated substantial reductions in class I MHC cell surface expression in most cell lines except in rodent cells where ICP47 is nonfunctional. The decrease in the level of class I MHC expression for ICP47 transduced cell lines ranged from 31-98% relative to negative controls. US11 decreased class I cell surface MHC by 67-96%. When both ICP47 and US11 are expressed in human cells, a further reduction of class I MHC was observed. Next, human A375 melanoma cells were tested to determine if the resulting reduction in cell surface class I MHC would reduce in vitro cytotoxicity by CTL. A375 cells expressing either ICP47 or US11 demonstrated a twofold to threefold reduction of specific lysis by primed CD8(+) CTL. These data clearly establish an ability to convey immune protection to human cells by viral genes. However, further analysis demonstrated that interferon (IFN)-gamma could reverse part or all of the downregulation of class I MHC induced by the ICP47 or US11 genes. The ICP47 and US11 genes, when expressed in target cells, decrease class I MHC presentation and as such might be used in strategies to create local immunosuppression against transgenes or allografts.
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PMID:Effective suppression of class I major histocompatibility complex expression by the US11 or ICP47 genes can be limited by cell type or interferon-gamma exposure. 1467 Jan 27


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