Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been shown that tumor-associated antigens (TAAs) can evoke tumor-specific T-cell-defined immune responses in cancer patients, thereby offering the possibility of treating patients with such antigens. To develop T-cell-based immunotherapeutic approaches for renal cell carcinoma (RCC), we studied the mRNA expression profile of the TAAs RAGE-1, tyrosinase, MAGE-1, MAGE-2, NY-ESO-1, Melan-A/MART-1, glycoprotein (gp) 75, gp100, beta-catenin, PRAME, and MUM-1 in 14 human RCC cell lines and in tissue specimens of 37 primary RCCs, 2 related metastases, and 33 specimens of normal renal epithelium. Reverse transcription-PCR was performed with TAA-reactive primers, and the specificity of the PCR products was confirmed by Southern blot and/or direct sequencing. PRAME (10 of 14 cell lines), RAGE-1 (7 of 14 cell lines), and gp75 (4 of 14 cell lines) antigens were expressed in a high percentage of RCC cell lines, although the level of TAA expression varied among the different RCC cell lines. However, low levels of TAA expression in RCC cells are sufficient for recognition by TAA-specific CTLs. Transcription of tyrosinase, Melan-A/MART-1, MAGE-1, MAGE-2, NY-ESO-1, gp100, beta-catenin, and MUM-1 was not detected in any RCC cell line. Approximately 50% of surgically removed neoplasias expressed at least one TAA. RAGE-1 mRNA expression was found in 8 of 39 (21%) RCC samples, PRAME mRNA expression was found in 15 of 39 (40%) RCC samples, and gp75 mRNA expression was found in 4 of 39 (11%) RCC samples, but the expression levels of these TAAs were heterogeneous in the different RCC lesions. One RCC specimen expressed MAGE-2, whereas transcription was not detected in any RCC specimen for MAGE-1, NY-ESO-1, tyrosinase, Melan-A/MART-1, gp100, beta-catenin, and MUM-1. The normal kidney epithelium samples were negative for any TAA tested. Thus, RAGE-1, PRAME, and gp75 expression is found with a different frequency in surgically removed lesions and in RCC cell lines, suggesting that a subgroup of RCC patients could be selected for immunotherapeutic strategies that may benefit from immunization against the RAGE-1, gp75, and/or PRAME antigens. However, additional targets for T-cell-based immunotherapy of RCC have yet to be identified.
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PMID:Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: candidates for T-cell-based immunotherapies? 975 17

Many melanoma epitopes are presented to cytotoxic T-lymphocytes (CTLs) by major histocompatibility complex (MHC) class I molecules, and it is reasonable to expect that the epitopes would be good substrates for the transporter associated with antigen processing (TAP), as TAP plays a major role in the transport of peptides into the endoplasmic reticulum (ER) for binding to MHC class I molecules. However, we have previously shown that several melanoma-associated epitopes, such as those derived from tyrosinase, gp100, MAGE-1 and MAGE-2 antigens, are in fact poor substrates for TAP. During the process of determining why these epitopes were capable of eliciting a strong CTL response, yet were poor substrates for TAP, it was observed that the epitopes possessed amino acids at their N-terminus that were deleterious for TAP binding as described for the peptide-binding motif for human TAP. We therefore postulated that the epitopes were transported by TAP as longer precursor molecules, and then trimmed in the ER to the appropriate size for presentation to T-cells. In an effort to test this hypothesis we synthesized a set of peptides, derived from the tyrosinase (YMNGTMSQV) and MAGE-1 (EADPTGHSY) epitopes, which possess N-terminal extensions of up to four amino acids. We show here that the longer peptides are indeed transported into the ER at a significantly higher level than the original epitopes. The data indicate that the longer melanoma-associated peptides are the preferred substrates for TAP, and further support the notion that peptides can be trimmed at the N-terminus in the ER during antigen processing.
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PMID:TAP prefers to transport melanoma antigenic peptides which are longer than the optimal T-cell epitope: evidence for further processing in the endoplasmic reticulum. 976 10

Blood lymphocytes from HLA-A*0201-subtyped melanoma patients and healthy controls were screened for the presence of T cells specific for HLA-A*0201-binding melanoma and viral peptide antigens by the enzyme-linked immunoSPOT (ELISPOT) assay. CD8(+) cells were tested for peptide-specific IFN-gamma release immediately after selection as well as after 2 weeks of in vitro stimulation. After in vitro stimulation, CD8(+) T cells specific for influenza were measured in all patients and controls, whereas these T cells could be detected among nonstimulated CD8(+) cells in only 52% of individuals. Similarly, T cells specific for EBV were more frequently measured among in vitro-stimulated than nonstimulated CD8(+) cells. In nonstimulated CD8(+) cells, T cells specific for MART-1/Melan-A, gp100, tyrosinase and CAMEL were present in 4 (33%), 1 (8%), 1 (8%) and 3 (25%) of 12 patients, respectively. Only MART-1/Melan-A-specific CD8(+) T cells were found in 1 (11%) of 9 healthy controls. CD8(+) T cells specific for MAGE-2 were not observed. After in vitro stimulation, CD8(+) T cells specific for MART-1/Melan-A could be demonstrated in 6 (46%) of 13 patients and 2 (20%) of 10 controls. CD8(+) T cells specific for gp100 were detected in 1 patient after in vitro stimulation. No CD8(+) T cells specific for tyrosinase, MAGE-2 or CAMEL could be measured after in vitro stimulation. These data show that the ELISPOT assay allows direct ex vivo detection of CD8(+) T cells specific for viral and melanoma antigens. Furthermore, the data show that the sensitivity of the ELISPOT assay to measure influenza- and EBV-specific CD8(+) T cells can be enhanced by a short in vitro stimulation step, whereas opposing effects on numbers of CD8(+) T cells specific for melanoma antigens have been observed.
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PMID:Detection and quantification of CD8(+) T cells specific for HLA-A*0201-binding melanoma and viral peptides by the IFN-gamma-ELISPOT assay. 1147 59

BACKGROUND: Metastatic, chemotherapy-resistant melanoma is an intractable cancer with a very poor prognosis. As to immunotherapy targeting metastatic melanoma, HLA-A2+ patients were mainly enrolled in the study in Western countries. However, HLA-A24+ melanoma patients-oriented immunotherapy has not been fully investigated. In the present study, we investigated the effect of dendritic cell (DC)-based immunotherapy on metastatic melanoma patients with HLA-A2 or A24 genotype. METHODS: Nine cases of metastatic melanoma were enrolled into a phase I study of monocyte-derived dendritic cell (DC)-based immunotherapy. HLA-genotype analysis revealed 4 cases of HLA-A*0201, 1 of A*0206 and 4 of A*2402. Enriched monocytes were obtained using OptiPreptrade mark from leukapheresis products, and then incubated with GM-CSF and IL-4 in a closed serum-free system. After pulsing with a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-2, MAGE-3 and MART-1 or MAGE-1) restricted to HLA-A2 or A24 and KLH, cells were cryopreserved until used. Finally, thawed DCs were washed and injected subcutaneously (s.c.) into the inguinal region in a dose-escalation manner. RESULTS: The mean percentage of DCs rated as lin-HLA-DR+ in melanoma patients was 46.4 +/- 15.6 %. Most of DCs expressed high level of co-stimulatory molecules and type1 phenotype (CD11c+HLA-DR+), while a moderate number of mature DCs with CD83 and CCR7 positive were contained in DC products. DC injections were well tolerated except for transient liver dysfunction (elevation of transaminases, Grade I-II). All 6 evaluable cases except for early PD showed positive immunological responses to more than 2 melanoma peptides in an ELISPOT assay. Two representative responders demonstrated strong HLA-class I protein expression in the tumor and very high scores of ELISPOT that might correlate to the regression of metastatic tumors. Clinical response through DC injections was as follows : 1CR, 1 PR, 1SD and 6 PD. All 59 DC injections in the phase I study were tolerable in terms of safety, however, the maximal tolerable dose of DCs was not determined. CONCLUSIONS: These results suggested that peptide cocktail-treated DC-based immunotherapy had the potential for utilizing as one of therapeutic tools against metastatic melanoma in Japan.
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PMID:Clinical response in Japanese metastatic melanoma patients treated with peptide cocktail-pulsed dendritic cells. 1567 80