Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peptides of melanosomal proteins have recently been shown to be recognized in an HLA-restricted mode by specific cytolytic T lymphocytes in melanoma patients. Dendritic antigen-presenting cells (DC) are considered to be the most effective stimulators of T cell responses, and the use of these cells has therefore been proposed to generate therapeutic responses to tumor antigens in cancer patients. We, therefore, generated DC from peripheral blood of normal donors in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4. Flow cytometric analysis of the cells during a 2-week culture revealed a loss of CD14 and CD34 expression, a concomittent increase of CD1a, CD11a,b and c, CD44, CD45, CD54, HLA-class I and II, and intermediate levels of CD26, CD80 and CD86. Cultured DC stimulated proliferation of allogeneic T cells and induced a marked, up to 20-fold, stimulation of T cell proliferation after pulsing with tetanus toxoid. To achieve independence of already-identified antigenic peptides presented in HLA class I-restricted fashion, which limits the general applicability of such peptides for vaccination of melanoma patients, we tested whether DC are transfectable with eukaryotic expression plasmids. DC transfected with two reporter genes (CAT, beta-galactosidase) using a liposome-based transfection technique, exhibited only low levels of enzymatically active proteins, but were able to degrade rapidly intracellular proteins and to process peptides efficiently. Chloramphenicol acetyltransferase as well as tyrosinase mRNA were detectable after transfection by reverse-transcriptase-polymerase chain reaction, and enzyme activities became measurable. Furthermore, DC transfected with the tyrosinase gene were able to induce specific T cell activation in vitro, indicating appropriate peptide processing and presentation in DC after transfection. These data suggest new approaches to future tumor vaccination strategies.
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PMID:Dendritic cells generated from peripheral blood transfected with human tyrosinase induce specific T cell activation. 748 49

The observation that allogeneic melanoma cells matched for particular HLA class I alleles stimulate T-cells isolated from patients suggests that widely shared antigens exist on these tumors. A transient expression system was developed for screening a melanoma complementary DNA library using the highly transfectable human kidney cell line 293. Using this system, large numbers of complementary DNA clones can be rapidly screened for the expression of antigens which stimulate T-cells. Tumor-infiltrating lymphocytes from patient 888, which recognized melanoma in the context of HLA-A24, were used to screen a complementary DNA library made from the autologous melanoma. Our results demonstrate that these tumor-infiltrating lymphocytes recognize tyrosinase, a gene previously shown to be recognized by T-cells only in the context of HLA-A2. These data demonstrate that a single antigen can be recognized in the context of two different class I HLA alleles. In addition, this study suggests that recognition of tyrosinase by antigen-specific T-cells may be involved in tumor rejection.
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PMID:Recognition of tyrosinase by tumor-infiltrating lymphocytes from a patient responding to immunotherapy. 820 28

TAP1 and TAP2 molecules are involved in the transport of peptides prior to their association with class I molecules and are mandatory for efficient antigen presentation. To investigate whether loss of expression of TAP1 or TAP2 is a likely mechanism of immune escape in malignant melanoma, TAP1 and TAP2 mRNA was analyzed by RT-PCR in 39 melanoma cell lines expressing at least 2 of the known melanoma-associated antigens, tyrosinase, Melan-A/MART-1, gp100, MAGE-1 and MAGE-3. All 39 cell lines expressed both TAP1 and TAP2 at the mRNA level. To investigate other factors potentially involved in immune escape, the expression of LMP2, LMP7, HLA class I molecules, beta2-microglobulin (beta2m) and specific HLA-A alleles was evaluated by RT-PCR and FACS analyses. All 39 cell lines expressed LMP2, LMP7 and beta2m. A single cell line (FM37) had lost the expression of class I molecules, and this same cell line showed loss of expression of the HLA-A2 heavy chain. No cell lines showed loss of expression of the HLA-A1 heavy chain. Based on our studies of in vitro established cell lines, loss of TAP1/2 or LMP2/7 expression does not appear to be a common mechanism of immune escape in malignant melanoma.
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PMID:Expression of transporter associated with antigen processing 1 and 2 (TAP1/2) in malignant melanoma cell lines. 905 59

In order to determine the possible use of uveal melanoma cell lines as stimulators in immunotherapy, we evaluated the expression of the human genes for MAGE-1, -2 and -3, gp100 and tyrosinase in uveal melanoma cell lines. mRNA expression of the MAGE-1, -2 and -3, gp100 and tyrosinase genes and the HLA class I specificity were determined in five primary and three metastatic uveal melanoma cell lines. Expression of the examined genes was heterogeneous in the primary and metastatic cell lines. The cell lines OCM-1 and OMM-1 expressed MAGE-1, -2 and -3, whereas EOM-3, MEL202, 92-1 and OMM-3 were negative for these antigens. gp100 was expressed in all cell lines, and tyrosinase in all but three (EOM-29, OMM-2 and OMM-3). Except for EOM-3, the HLA-A type of all the cell lines could be determined by complement-dependent microlymphocytotoxicity assay. Since at least two melanoma-associated antigens can be found in uveal melanoma cell lines, as well as the HLA class I molecules, these cell lines may be applicable as immunogens for specific immunotherapy against metastatic uveal melanoma.
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PMID:Expression of MAGE, gp100 and tyrosinase genes in uveal melanoma cell lines. 950 71

During the last 6 years significant progress has been achieved in the identification of melanoma-associated antigens recognized by cytotoxic T lymphocytes. These antigens belong the three main groups: tumor-associated testis-specific antigens (MAGE, BAGE, GAGE and PRAME), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2) and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). In this review, we have summarized the available data concerning the characterization of melanoma-associated antigens with focus on their immunogenic and protective properties. The development of a strong immune response against differentiation antigens is limited by the existence of tolerance against these 'self' antigens, permitting the involvement of only T cells with low affinity T cell receptors. Among the melanoma differentiation antigens, only gp100 has been shown to be a tumor regression antigen. The testis-specific antigens such as MAGE and PRAME should potentially be highly immunogenic antigens. They contain several potential HLA class I binding epitopes and are present only in the testes which are not accessible to the cells of the immune system due to the lack of direct contact with the immune cells and the lack of HLA class I expression on the surface of germ cells. But only 2 patients have been found who responded to these antigens in vivo, indicating their genuinely low immunogenicity. A comparison of the predicted secondary structures of these two groups of antigens (testis-specific and differentiation antigens) revealed enrichment of long alpha-helical stretches in the testis-specific antigens. We hypothesize that such highly organized structures could diminish the efficiency of the protein unfolding--a necessary step in the proteolytic cleavage by proteasomes--and, therefore, could be responsible for the low immunogenicity of these proteins. In this case, modifications decreasing the stability of these proteins might be a means to improve the immune response against these potentially therapeutically useful antigens.
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PMID:The immunogenic properties of melanoma-associated antigens recognized by cytotoxic T lymphocytes. 961 97

Expression of HLA class I molecules is essential for the recognition of tumor cells by CD8+ T cells. In this study, 48 bioptic samples of 42 patients in all stages of melanoma were investigated after short-time cultivation of tumor cells. To confirm melanocytic origin of cultured cells, samples were screened for mRNA expression of melanoma markers gp100, tyrosinase, MAGE-3, MelanA, and MUC18 by reverse transcriptase-polymerase chain reaction. Surface expression of specific HLA-A and -B allospecificities on melanoma cells were analyzed with a standard microcytotoxicity assay after stimulation with interferon (IFN)-alpha and compared with the background found in peripheral blood mononuclear cells from the corresponding patients. Immunohistochemistry and flow cytometry confirmed specific losses in cases where the appropriate monoclonal antibodies were available. The level of expression of HLA-I, HLA-II, and intercellular adhesion molecule 1 antigens on melanoma cells cultured in the presence or absence of IFN-alpha and IFN-gamma was determined cytofluorometrically. All cell cultures tested were found to be positive for one or more melanocytic markers by reverse transcriptase-polymerase chain reaction. The specific HLA-I alleles on the cultured cells were detectable in 45 of 48 samples. In 11 cases a specific loss of one HLA-I allele was observed (2 x A2, B7, B8, B18, 4XB44, B47, B49). Ten of these samples were derived from locoregional lymphnode metastases or from distant metastatic tumors. Only one sample from a primary melanoma showed a specific loss of HLA-I (B47). IFN-alpha upregulated expression of HLA-I up to 4-fold. IFN-gamma enhanced the appearance of HLA-II up to 35-fold and the expression of intercellular adhesion molecule 1 up to 40-fold. Selective loss of HLA-I allospecificities might be a major step in tumor progression.
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PMID:Higher frequency of selective losses of HLA-A and -B allospecificities in metastasis than in primary melanoma lesions. 974 Feb 47

During the last 7 years significant progress has been made in the identification of melanoma-associated antigens recognized by cytotoxic T lymphocytes (CTL). These antigens belong to three main groups: cancer/testis-specific antigens (MAGE, BAGE, GAGE, PRAME and NY-ESO-1), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2), and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). In this review we have summarized the available data concerning the characterization of melanoma-associated antigens, focusing on their immunogenic and protective properties. The development of a strong immune response to differentiation antigens is limited by the existence of tolerance to these "self"-antigens, permitting the involvement of only T cells with low affinity T-cell receptors. Among the melanoma differentiation antigens, only gp100 has been shown to be a tumor regression antigen. The cancer/testis-specific antigens such as MAGE and PRAME should potentially be highly immunogenic antigens. They contain several potential HLA class I binding epitopes and are present only in the testes, which are not accessible to the cells of the immune system owing to the lack of direct contact with the immune cells and the lack of HLA class I expression on the surface of germ cells. But only two patients have been found who responded to these antigens in vivo, indicating their genuinely low immunogenicity. A comparison of the predicted secondary structures of these two groups of antigens (cancer/testis-specific and differentiation antigens) revealed enrichment of long alpha-helical stretches in the cancer/testis-specific antigens. We hypothesize that such highly organized stable structures could, first, reduce denaturation of the protein and, thus, ubiquitinylation as a degradation signal, and, second, diminish the efficiency of the protein unfolding - a necessary step in the proteolytic cleavage by proteasomes. High structural stability could therefore be responsible for the low immunogenicity of these proteins. In this case, modifications decreasing the stability of these proteins might be a means of improving the immune response to these potentially therapeutically useful antigens.
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PMID:Melanoma-associated antigens recognized by cytotoxic T lymphocytes. 974 May 4

We have shown the presence of tyrosinase-reactive T cells in the peripheral blood of melanoma patients, who had been in remission after treatment with IL-2-containing regimens. In this consecutive study, we analyzed the T-cell response to various peptides derived from tyrosinase in serial blood samples obtained from 7 stage-IV melanoma patients before, during and following treatment. All patients were treated within a randomized trial (EORTC 18951) with cisplatin (CDDP), dacarbazine (DTIC), interferon-alpha (IFN-alpha) +/- interleukin-2 (IL-2). Using an ELISPOT assay detecting peptide-specific IFN-gamma release, we measured the T-cell response to 4 different HLA class I-binding peptide epitopes derived from tyrosinase containing an HLA-A2.1-, HLA-A24- or HLA-B44-binding motif in peripheral-blood mononuclear cells (PBMC). In one patient, tyrosinase-reactive T cells were detected before therapy. In 4 out of 7 patients, tyrosinase-reactive T cells against both HLA-A2.1-binding peptides and the B44-binding peptide became detectable at frequencies of up to 30 in 5 x 10(5) lymphocytes following treatment. These patients received CDDP, DTIC and IFN-alpha, 2 of them without IL-2 and 2 with IL-2, resulting in one complete remission and 3 partial remissions. Two patients relapsed 8 and 9 months after treatment. At the time of relapse, no T cells reactive with tyrosinase were detectable. Our results show that high frequencies of tyrosinase-reactive T cells in the peripheral blood of melanoma patients can be induced by chemotherapy in combination with IFN-alpha, regardless of concomitant IL-2 administration.
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PMID:Induction of tyrosinase-reactive T cells by treatment with dacarbazine, cisplatin, interferon-alpha +/- interleukin-2 in patients with metastatic melanoma. 993 27

Antigenic peptides have been found associated with heat shock proteins (HSP) including cytoplasmic HSP70 and heat shock cognate protein 70 as well as the endoplasmic reticulum-resident glucose-regulated protein 94. Recently, HSP70 transfection has been reported to increase MHC class I cell surface expression and antigen presentation on mouse melanoma B16 cells (Wells et al., Int. Immunol. 1998. 10: 609). To analyze the effect of HSP70 on MHC class I cell surface expression and lysability of target cells we transfected a human melanoma cell line with the rat Hsp70-1 gene using the Tet-On system for conditional overexpression of HSP70. Induction of HSP70 did not increase cell surface expression of HLA class I molecules in general or individual HLA-A and B antigens in particular. Nonetheless, induction of HSP70 enhanced susceptibility of these cells to lysis by allospecific CTL. The same effect was observed using an HLA-A2-restricted tyrosinase-specific CTL clone after pulsing the tyrosinase-negative target cells with the specific peptide. Thus, HSP70 induction can increase killing by CTL without affecting MHC class I cell surface expression or antigen processing. This effect of HSP70 appears to be different from the commonly found protection exerted by HSP70 against stress like heat shock, and might be mediated by improving CTL-induced apoptosis.
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PMID:Enhanced susceptibility to cytotoxic T lymphocytes without increase of MHC class I antigen expression after conditional overexpression of heat shock protein 70 in target cells. 1060

The analysis of immune responses of patients with melanoma has led to the identification of melanoma-associated antigens targeted by T cells. Cytotoxic T lymphocytes recognize peptides from melanoma-associated antigens presented on the cancer cell surface in the context of HLA class I molecules. Immunodominant melanoma-associated antigen epitopes are being evaluated for their ability to immunize patients with advanced melanoma. However, these vaccination efforts are limited by the extensive polymorphism of the HLA class I heavy chain, which occurs in functional domains of the molecule. Patients with melanoma with the HLA-A-24 phenotype were recruited for vaccination with the peptide AFLPWHRLF from the melanoma-associated antigen tyrosinase. This peptide is recognized in association with HLA-A*2402. The HLA-A24 family includes at least 15 alleles whose frequency and ability to present the same peptide are unknown. The distribution of HLA-A24 alleles was studied in a melanoma population for the practical purpose of identifying patients suitable for vaccination with HLA-A*2402 epitopes. An HLA-A locus-specific polymerase chain reaction method followed by sequencing was developed to determine the HLA-A alleles in genomic DNA. HLA-A 24 was also typed in healthy persons of various ethnic backgrounds to further explore the HLA-A24 family. In white persons, the HLA-A*2402 allele was most common (in 85% of white persons and in 97% of the patients with melanoma). Fewer persons carried the HLA-A*2403 allele (13% in all samples, 3% in melanoma patients). Finally, two new alleles, HLA-A*2422 and HLA-A*24 null, were identified. These results suggest that vaccination with HLA-A*2402-associated epitopes has the potential for broad use in this patient population.
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PMID:Frequency of human leukocyte antigen-A 24 alleles in patients with melanoma determined by human leukocyte antigen-A sequence-based typing. 1074 55


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