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Yutaka Kawakami - One of the best experts on this subject based on the ideXlab platform.

  • identification of a shared hla a 0201 restricted t cell epitope from the melanoma antigen tyrosinase related protein 2 trp2
    Cancer Research, 1998
    Co-Authors: Maria R Parkhurst, Ellen B Fitzgerald, Alessandro Sette, Scott Southwood, Steven A Rosenberg, Yutaka Kawakami
    Abstract:

    Abstract Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas. This protein has been identified as a melanoma antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among melanoma patients in the United States is low (∼6% for HLA-A31 and ∼2% for HLA-A33) compared with that of HLA-A*0201 (∼46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ melanoma patients in vitro. One peptide, TRP2(180–188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ melanomas. TRP2(180–188) is identical to a previously identified TRP2 epitope recognized by murine melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression.

  • identification of a shared hla a 0201 restricted t cell epitope from the melanoma antigen tyrosinase related protein 2 trp2
    Cancer Research, 1998
    Co-Authors: Maria R Parkhurst, Ellen B Fitzgerald, Alessandro Sette, Scott Southwood, Steven A Rosenberg, Yutaka Kawakami
    Abstract:

    Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas. This protein has been identified as a melanoma antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among melanoma patients in the United States is low (approximately 6% for HLA-A31 and approximately 2% for HLA-A33) compared with that of HLA-A*0201 (approximately 46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ melanoma patients in vitro. One peptide, TRP2(180-188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ melanomas. TRP2(180-188) is identical to a previously identified TRP2 epitope recognized by murine melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression.

Lucy R Wedderburn - One of the best experts on this subject based on the ideXlab platform.

  • hla dpb1 associations differ between drb1 03 positive anti jo 1 and anti pm scl antibody positive idiopathic inflammatory myopathy
    Rheumatology, 2009
    Co-Authors: Hector Chinoy, Debbie Payne, Kate V Poulton, Zoe Betteridge, Harsha Gunawardena, Noreen Fertig, Chester V. Oddis, Neil Mchugh, J Davidson, Lucy R Wedderburn
    Abstract:

    OBJECTIVE: The HLA 8.1 ancestral haplotype (HLA-B*08/DRB1*03/DQA1*05/DQB1*02) is associated with adult/juvenile idiopathic inflammatory myopathy (IIM), but confers a greater strength of association in patients possessing anti-Jo-1 or anti-PM-Scl antibodies. The HLA-DPB1 gene is centromeric to other HLA class II loci and separated by a recombination hotspot. We investigated whether HLA-DPB1 associations differ between anti-Jo-1 and anti-PM-Scl antibody-positive IIM cases. METHODS: Two hundred and thirty-three adult IIM patients (73% females, 49.4 +/- 13.6 years) with PM (n = 89), DM (n = 88) and myositis associated with another CTD (n = 55) and 85 juvenile DM patients (75% females, 6.2 +/- 3.6 years) were compared with 678 UK Caucasian controls. Patients/controls were genotyped for HLA-DPB1 and DRB1 alleles. Myositis-specific and associated antibodies were identified in cases using immunoprecipitation. RESULTS: HLA-DPB1*0101 was associated with IIM overall [22 vs 13% controls, corrected probability (P(corr)) = 2 x 10(-03); odds ratio (OR) 2.0; 95% CI 1.4, 2.9], PM (P(corr) = 7 x 10(-03); OR 2.5; 95% CI 1.5, 4.4) and anti-Jo-1 (P(corr) = 3 x 10(-5); OR 4.1; 95% CI 2.1, 7.8). No significant DPB1*0101 difference was present between anti-PM-Scl cases and controls. The HLA-DPB1*0101 association in IIM overall cases was dependent on the presence of DRB1*03. A number of HLA-DRB1*03/DPB1 haplotypes were identified, but only DRB1*03/DPB1*0101 was associated with anti-Jo-1 antibody-positive cases. CONCLUSIONS: The HLA-DRB1*03/DPB1*0101 haplotype is a risk factor for anti-Jo-1 antibody-positive IIM. Thus, although DRB1*03 is strongly associated with possession of either anti-Jo-1 or anti-PM-Scl, differing antibody associations are observed at the HLA-DPB1 locus.

A Lindemann - One of the best experts on this subject based on the ideXlab platform.

  • phase i study in melanoma patients of a vaccine with peptide pulsed dendritic cells generated in vitro from cd34 hematopoietic progenitor cells
    International Journal of Cancer, 2000
    Co-Authors: Andreas Mackensen, Giulio C Spagnoli, Birgit Herbst, Jili Chen, Gabriele Kohler, Christoph Noppen, Wolfgang Herr, Vincenzo Cerundolo, A Lindemann
    Abstract:

    Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that can be used for vaccination purposes, to induce a specific T-cell response in vivo against melanoma-associated antigens. We have shown that the sequential use of early-acting hematopoietic growth factors, stem cell factor, IL-3 and IL-6, followed by differentiation with IL-4 and granulocyte-macrophage colony-stimulating factor allows the in vitro generation of large numbers of immature DCs from CD34(+) peripheral blood progenitor cells. Maturation to interdigitating DCs could specifically be induced within 24 hr by addition of TNF-alpha. Here, we report on a phase I clinical vaccination trial in melanoma patients using peptide-pulsed DCs. Fourteen HLA-A1(+) or HLA-A2(+) patients received at least 4 i.v. infusions of 5 x 10(6) to 5 x 10(7) DCs pulsed with a pool of peptides including either MAGE-1, MAGE-3 (HLA-A1) or Melan-A, gp100, tyrosinase (HLA-A2), depending on the HLA haplotype. A total of 83 vaccinations were performed. Clinical side effects were mild and consisted of low-grade fever (WHO grade I-II). Clinical and immunological responses consisted of anti-tumor responses in 2 patients, increased melanoma peptide-specific delayed-type hypersensitivity reactions in 4 patients, significant expansion of Melan-A- and gp100-specific cytotoxic T lymphocytes in the peripheral blood lymphocytes of 1 patient after vaccination and development of vitiligo in another HLA-A2(+) patient. Our data indicate that the vaccination of peptide-pulsed DCs is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects.

  • phase i study in melanoma patients of a vaccine with peptide pulsed dendritic cells generated in vitro from cd34 hematopoietic progenitor cells
    International Journal of Cancer, 2000
    Co-Authors: Andreas Mackensen, Giulio C Spagnoli, Birgit Herbst, Jili Chen, Gabriele Kohler, Christoph Noppen, Wolfgang Herr, Vincenzo Cerundolo, A Lindemann
    Abstract:

    Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that can be used for vaccination purposes, to induce a specific T-cell response in vivo against melanoma-associated antigens. We have shown that the sequential use of early-acting hematopoietic growth factors, stem cell factor, IL-3 and IL-6, followed by differentiation with IL-4 and granulocyte-macrophage colony-stimulating factor allows the in vitro generation of large numbers of immature DCs from CD34+ peripheral blood progenitor cells. Maturation to interdigitating DCs could specifically be induced within 24 hr by addition of TNF-α. Here, we report on a phase I clinical vaccination trial in melanoma patients using peptide-pulsed DCs. Fourteen HLA-A1+ or HLA-A2+ patients received at least 4 i.v. infusions of 5 × 106 to 5 × 107 DCs pulsed with a pool of peptides including either MAGE-1, MAGE-3 (HLA-A1) or Melan-A, gp100, tyrosinase (HLA-A2), depending on the HLA haplotype. A total of 83 vaccinations were performed. Clinical side effects were mild and consisted of low-grade fever (WHO grade I–II). Clinical and immunological responses consisted of anti-tumor responses in 2 patients, increased melanoma peptide-specific delayed-type hypersensitivity reactions in 4 patients, significant expansion of Melan-A- and gp100-specific cytotoxic T lymphocytes in the peripheral blood lymphocytes of 1 patient after vaccination and development of vitiligo in another HLA-A2+ patient. Our data indicate that the vaccination of peptide-pulsed DCs is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects. Int. J. Cancer 86:385–392, 2000. © 2000 Wiley-Liss, Inc.

Hector Chinoy - One of the best experts on this subject based on the ideXlab platform.

  • hla dpb1 associations differ between drb1 03 positive anti jo 1 and anti pm scl antibody positive idiopathic inflammatory myopathy
    Rheumatology, 2009
    Co-Authors: Hector Chinoy, Debbie Payne, Kate V Poulton, Zoe Betteridge, Harsha Gunawardena, Noreen Fertig, Chester V. Oddis, Neil Mchugh, J Davidson, Lucy R Wedderburn
    Abstract:

    OBJECTIVE: The HLA 8.1 ancestral haplotype (HLA-B*08/DRB1*03/DQA1*05/DQB1*02) is associated with adult/juvenile idiopathic inflammatory myopathy (IIM), but confers a greater strength of association in patients possessing anti-Jo-1 or anti-PM-Scl antibodies. The HLA-DPB1 gene is centromeric to other HLA class II loci and separated by a recombination hotspot. We investigated whether HLA-DPB1 associations differ between anti-Jo-1 and anti-PM-Scl antibody-positive IIM cases. METHODS: Two hundred and thirty-three adult IIM patients (73% females, 49.4 +/- 13.6 years) with PM (n = 89), DM (n = 88) and myositis associated with another CTD (n = 55) and 85 juvenile DM patients (75% females, 6.2 +/- 3.6 years) were compared with 678 UK Caucasian controls. Patients/controls were genotyped for HLA-DPB1 and DRB1 alleles. Myositis-specific and associated antibodies were identified in cases using immunoprecipitation. RESULTS: HLA-DPB1*0101 was associated with IIM overall [22 vs 13% controls, corrected probability (P(corr)) = 2 x 10(-03); odds ratio (OR) 2.0; 95% CI 1.4, 2.9], PM (P(corr) = 7 x 10(-03); OR 2.5; 95% CI 1.5, 4.4) and anti-Jo-1 (P(corr) = 3 x 10(-5); OR 4.1; 95% CI 2.1, 7.8). No significant DPB1*0101 difference was present between anti-PM-Scl cases and controls. The HLA-DPB1*0101 association in IIM overall cases was dependent on the presence of DRB1*03. A number of HLA-DRB1*03/DPB1 haplotypes were identified, but only DRB1*03/DPB1*0101 was associated with anti-Jo-1 antibody-positive cases. CONCLUSIONS: The HLA-DRB1*03/DPB1*0101 haplotype is a risk factor for anti-Jo-1 antibody-positive IIM. Thus, although DRB1*03 is strongly associated with possession of either anti-Jo-1 or anti-PM-Scl, differing antibody associations are observed at the HLA-DPB1 locus.

  • hla dpb1 0101 discriminates between anti jo 1 and anti pm scl antibody positive uk caucasians with idiopathic inflammatory myopathy
    In: American College of Rheumatology; 2007. p. 56:S653., 2007
    Co-Authors: Hector Chinoy, Debbie Payne, Noreen Fertig, Chester V. Oddis, Kay Poulton, Ollier W E R, R G Cooper
    Abstract:

    Purpose: In the IIMs, HLA-DRB1*03 is strongly associated with possession of anti-Jo-1 or -PM-Scl antibodies (Abs). Given the other clinical phenotype differences between these subgroups, we hypothesise that genetic differences also exist. The HLA-DPB1 region has not been investigated to date in the IIMs. We therefore investigate the role of HLA-DPB1 in UK Caucasians polymyositis (PM) and dermatomyositis (DM) patients, and examine the relationship of DPB1 with HLA-DRB1 and myositis specific/associated Abs (MSA/MAAs).Methods: 177 UK Caucasians with PM (n=89, 27% male, 51+/- 13.7 years) and DM (n=88, 31% male, 49+/- 14.6 years) defined with definite/probable disease (Bohan and Peter, 1975), were compared to 678 ethnically matched controls. DNA were genotyped at HLA-DPB1 and DRB1 using a commercial sequence specific oligonucleotide kit. The type of detectable circulating MSA (anti-Jo-1, PL-7, PL-12, EJ, OJ, KS, Mi-2, SRP) and MAA (U1/U3-RNP, Ku, PM-Scl) was also established.Results: There was a significant overall difference between cases and controls for HLA-DPB1 (p=0.002) and DRB1 (p=0.0001). Linkage disequilibrium (LD) was noted between HLA-DPB1*0101 and DRB1*03 in controls (D?=0.67). HLA-DPB1*0101 and DRB1*03 were significant risk factors in PM and anti-Jo-1 Ab positive patients. Using multivariate logistic regression, PM and anti-Jo-1 DPB*0101 associations were lost after adjusting for DRB1*03, which remained highly significant. No interaction was noted between these two alleles and no gender effect was noted. Of note, 10/10 PM-Scl Ab positive patients had at least one copy of DRB1*03, but only 1/10 possessed a copy of DPB1*0101. DPB*0301 was a possible protective factor in cases overall (12% cases vs. 20% controls, uncorrected p=0.02, OR 2.5, 0.3-0.9). After allowing for the presence of DPB1*0101, no further significant associations were noted.Conclusions: HLA-DPB1*0101 is significantly associated with PM and anti-Jo-1 positive patients, although the association appears due to LD with DRB1*03. However, PM-Scl, the Ab with the strongest DRB1*03 association, is not associated with DPB*0101. This is the first data from the HLA region to genetically discriminate anti-Jo-1 from anti-PM-Scl Ab positive IIM patients.HLA phenotype Case group % Correctedp Oddsratio 95%confidenceintervalDPB*0101 PM 27 0.007 2.5 1.4-4.4 DM 20 NS 1.8 0.9-3.2 Jo-1 43 1.5 x 10-6 5.2 2.5-10.4 PM-Scl 10 NS 0.8 0.2-5.6DRB1*03 PM 62 1.6 x 10-11 4.0 2.7-6.2 DM 45 0.007 2.0 1.3-3.2 Jo-1 88 6.9 x 10-19 18.0 7.9-47.6 PM-Scl 97 1.9 x 10-13 69.1 11.2-2829Key: NS=Non-significant. For controls, DPB*0101 =13%, DRB1*03=29%

Maria R Parkhurst - One of the best experts on this subject based on the ideXlab platform.

  • identification of a shared hla a 0201 restricted t cell epitope from the melanoma antigen tyrosinase related protein 2 trp2
    Cancer Research, 1998
    Co-Authors: Maria R Parkhurst, Ellen B Fitzgerald, Alessandro Sette, Scott Southwood, Steven A Rosenberg, Yutaka Kawakami
    Abstract:

    Abstract Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas. This protein has been identified as a melanoma antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among melanoma patients in the United States is low (∼6% for HLA-A31 and ∼2% for HLA-A33) compared with that of HLA-A*0201 (∼46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ melanoma patients in vitro. One peptide, TRP2(180–188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ melanomas. TRP2(180–188) is identical to a previously identified TRP2 epitope recognized by murine melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression.

  • identification of a shared hla a 0201 restricted t cell epitope from the melanoma antigen tyrosinase related protein 2 trp2
    Cancer Research, 1998
    Co-Authors: Maria R Parkhurst, Ellen B Fitzgerald, Alessandro Sette, Scott Southwood, Steven A Rosenberg, Yutaka Kawakami
    Abstract:

    Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas. This protein has been identified as a melanoma antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among melanoma patients in the United States is low (approximately 6% for HLA-A31 and approximately 2% for HLA-A33) compared with that of HLA-A*0201 (approximately 46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ melanoma patients in vitro. One peptide, TRP2(180-188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ melanomas. TRP2(180-188) is identical to a previously identified TRP2 epitope recognized by murine melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression.