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STUDY ON MACHINERY HLA CLASS I DOWNREGULATION ON MELANOMA CELLS.

Research Project

Project/Area Number 09670888
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionKUMAMOTO UNIVERSITY

Principal Investigator

KAGESHITA Toshiro  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE,DEPARTMENT OF DERMATOLOGY,ASSISTANT PROFESSOR., 医学部・附属病院, 講師 (20152605)

Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1998: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsMELANOMA / HLA CLASS I / LMP / TAP / HlaClassI / HlaClassI allete / HLS Class I allele
Research Abstract

(1) Frequency of HLA Class I downregulation in melanoma lesions
The aim of this study was to investigate the expression of HLA Class I antigens in surgically removed melanoma lesions. To this end 32 primary and 11 metastatic lesions were stained in the immunoperoxidase reaction with monoclonal antibodies(mAb) to monomorphic, locus specific and polymorphic antigenic determinants. The intensity of staining of melanoma cells was compared to that of keratinocytes surrounding the tumor nest. The patients' HLA phenotype was determined utilizing the conventional lymphocytotoxicity assay. About 20% of primary and about 50% of metastatic lesions were not stained or were stained with reduced intensity by mAb to monomorphic and locus specific antigenic determinants. Moreover about 40% of primary and about 60% of metastatic lesions were not stained or were stained with low intensity, by mAb to HLA Class I allospecificities. These results indicate that the frequency of abnormalities in HLA Class I a … More ntigen expression is high in melanoma lesions. These abnormalities are likely to have a negative impact on T cell based immunotherapy, since they provide melanoma cells with a mechanism to escape from destruction by cytotoxic T cells.
(2) Machinery of HLA Class I downregulation in melanoma cells.
The expression of the proteasome subunits LMP2 and LMP7, the MHC-encoded transporter subunits TAP1 and TAP2 and HLA Class antigens was tested by immunoperoxidase staining in melanoma lesions, since these molecules play an important role in the presentation of melanoma associated antigen derived peptides to cytotoxic T cells. LMP2 was less frequentlt expressed than LMP7 in primary and metastatic lesions. TAP1, TAP2 and HLA Class I antigen expression was more frquently downregulated in metastatic than in primary melanoma lesions. A synchronous downregulation of TAP1, TAP2 and HLA Class I antigen expression was observed in about 60% of primary and metastatic melanoma lesions. Moreover, these downregulation in primary lesions was significantly associated with their thickness, with the stage of the disease, with a reduced time to disease progression and with a reduced survival. These results suggest that TAP plays an important role in HLA Class I downregulation in melanoma cells and in the clinical course of the disease, probably by providing melanoma cells with a mechanism to escape from CTL recognition during disease progression. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (48 results)

All Other

All Publications (48 results)

  • [Publications] Kageshita T, et al: "HLA Class I antigens in Japanese patients with melanoma" J. Immunother.19. 428-432 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Molecular genetic analysis of HLA class II alleles in Japanese patients with melanoma." Tissue Antigens.49. 466-470 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Serum levels of sICAM-1 and S-S-Cysteinyldopa as markers of melanoma progression." Melanoma Res.7. 58-62 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Beta z-microglobulin gene mutations in human melanoma cells:Molecular characterization and implications for immune surveillance." Melanoma Res.(Suppl, 2). 7. S67-S74 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Differential expression of MART-1 in primary and metastatic melanoma lesions." J. Immunother.20. 460-465 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Characterization of rabbit antisera elicited with human LMP2 and LMP7-specific peptide and recommbinant proteins" Tissue Antigens. 50. 567-575 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Development and characterization of mouse anti-human LMP2, LMP7, TAP1 and TAP2 monoclonal antibodies." Tissue Antigens. 51. 129-140 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Characterization of human anti-HMW-MAA single chain FV antibodies isolated from a phase display antibody library." Cancer Res.58. 2417-2425 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Hypercalcemia in MM arising in congenital giant pigmented neves." Dermatology. 197. 65-68 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Limited diversity of human sc FV fragments isolated by panning a synthetic phase display sc FV library with cultured human melanoma cells." J. Immunol.161. 2968-2976 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Low frequency of neutralizing antibodies against natural IFN-β during adjuvant therapy for Japanese patients with melanoma." J. Dermatol. Sci. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Hypercelcemia in melanoma patients associated with increased levels of parathyroid hormone related protein." Melanoma Res. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Increased serum levels of 5-s-Cysteinyldopa and ICAM-1 in patient with a uterine amelanotic netustasis, from a primary vaginal melanoma." Gynecologic. Oncology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "Down regulation of HLA class I antigens processing molecules in malignant melanoma." Am. J. Pathol.(in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "HLA:Genetic diversity of HLA functional and medical implication, Vol II" Charon D., 777 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "HLA:Genetic diversity of HLA functional and medical implication, Vol I" Charon D., (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T, et al: "HLA:Genetic diversity of HLA functional and medical implication, Vol II" Charon D., 777 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Naruse T,Hirai S,Horikoshi T,Nakagawa H,Tamaki K,Hayashibe K,Ichihashi M,Nakayama J,Hori Y,Ozawa A,Miyahara M,Ohkido M,Inoko H,Ono T.: "HLA class I antigens in Japanese patients with melanoma." J.Immunother.19. 428-432 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Naruse T,Hirai S,Ono T,Horikoshi T,Nakagawa H,Tamaki K,Hayashibe K,Ichihashi M,Nakayama J,Hori Y,Ozawa A,Miyahara M,Ohkido M,Inoko H.: "Molecular genetic analysis of HLA class II alleles in Japanese patients with melanoma." Tissue Antigens.49. 466-470 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hirai S,Kageshita T,Kimura T,Tsujisaki M,Imai K,Wakamatsu K,Ito S,Ono T.: "Serum levels of sICAM-1 and 5-S-Cysteinyldopa as markers of melanoma progression." Melanoma Res.7. 58-62 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hicklin DJ,Dellaratta DV,Kishore R,Liang B,Kageshita T,Ferrone S.: "Beta 2-microglobulin gene mutations in human melanoma cells : Molecular characterization and implications for immune surveillance." Melanoma Res.7 (Suppl 2). S67-S74 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Kawakami Y,Hirai S,Ono T.: "Differential expression of MART-1 in primary and metastatic melanoma lesions." J.Immunother.20. 460-465 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Dellaratta D,Hicklin DJ,Kishore R,Kageshita T,Ferrone S.: "Characterization of rabbit antisera elicited with human LMP2 and LMP7-specific peptides and recommbinant proteins." Tissue Antigens.50. 567-575 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Hirai S,Ono T,Ferrone S.: "Comparison of the reactivity of frozen and formalin-fixed, paraffin-embedded sections of melanoma lesions with anti-HLA Class I mAb. : Genetic diversity of HLA functional and medical implication. Volume II (ed.Charron D.) EDK,Paris." 737-739 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hicklin DJ,Kageshita T,Dellaratta D,Ferrone S.: "Transporter associated with antigen processing (TAP) downregulation in human melanoma cells. : Genetic diversity of HLA functional and medical implication. Volume II (ed.Charron D.) EDK,Paris." 742-744 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Garrido F,Cabera T,Accolla RS,Bensa JC,Bodmer W,Dohr G,Drouer M,Faucher R,Ferrara GB, Ferrone S,Giacomini P,Kageshita T,Koopman L,Maio M,Marincola F,Mazzilli C,Morel PA,Murra A,Papasteriades CRH,Salvaneschi L,Stern PL,Ziegler A.: "HLA and cancer : 12th International Histocompatibility Workshop study. : Genetic diversity of HLA functional and medical implication. Volume I (ed.Charron D.) EDK,Paris." 445-452 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kishore R,Hicklin DJ,Dellaratta DV,Golde U,Kageshita T,Seliger B,Ferrone S.: "Development and characterization of mouse anti-human LMP2, LMP7, TAP1 and TAP2 monoclonal antibodies." Tissue Antigens.51. 129-140 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Desai SA,Wang X,Noronha EJ,Kageshita T,Ferrone S.: "Characterization of human anti-high molecular weight-melanoma associated antigen single chain Fv antibodies isolated from a phage display antibody library." Cancer Res.58. 2417-2425 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsui T,Kageshita T,Ishihara T,Tomiguchi S,Takahashi M,Ono T.: "Hypercalcemia in malignant melanoma arising in congenital giant pigmented nevus- a case showing increasing serum level of parathyroid hormone-related protein (PTHrP) -" Dermatology.197. 65-68 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Noronha EJ,Wang X,Desai SA,Kageshita T,Ferrone S.: "Limited diversity of human scFv : fragments isolated by panning a synthetic phage display scFv library with cultured human melanoma cells." J.Immunol.161. 2968-2976 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Yamamoto A,Yamazaki N,Ishihara K,Ono T.: "Low frequency of neutralizing antibodies against natural interferon-beta during adjuvant therapy for Japanese patients with melanoma." J.Dermatol.Sci.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Matsui T,Hirai S,Fukuda Y,Ono T.: "Hypercalcemia in melanoma patients associated with increased levels of parathyroid hormone related protein." Melanoma Res.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Suenaga Y,Katabuchi H,Okamura H,Kageshita T,Ono T.: "Increased serum levels of 5-S-Cysteinyldopa and intercellular adhesion molecule-1 in a patient with a uterine amelanotic metastasis from a primary vaginal malignant melanoma." Gynecologic.Oncology.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,Hirai S,Ono T,Hicklin DJ,Ferrone S.: "Downregulation of HLA class I antigens processing molecules in malignant melanoma. Association with disease progression." Am.J.Pathol.(in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kageshita T,et al.: "HLA class I antigens in Japanese patients with melanoma." J.Immunother.19. 428-432 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kageshita T,et al.: "Molecular genetic analysis of HLA class II alleles in Japanese patients with melanoma" Tissue Antigens.49. 466-470 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kageshita T,et al.: "Beta 2-microglobulin gene mutations in human melanoma cells:Molecular characterization and implications for immune surveillance." Melanoma Res.7(suppl 2). S67-S74 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kageshita T,et al.: "Differential expression of MART-1 in primary and metastatic melanoma lesions." J.Immunother.20152605. 460-465 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kageshita T,et al.: "Characterization of rabbit antisera elicited with human LMP2-and LMP7-specific peptides and recombinant proteins." Tissue Antigens.50. 567-575 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kageshita T,et al.: "Development and characterization of mouse anti-human LMP2.LMP7,TAP1 and TAP2 monoclonal antibodies." Tissue Antigens.51. 129-140 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kageshita T,et al.: "HLA:Genetic diversity of HLA functional and medical implication." Charron D., 777 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hicklin D.: "Development and characterization of rabbit antisera to human MHC-inked transporters associated with antigen processing." Tissue Antigens.48. 38-46 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kageshita T.: "HLA class I antigens in Japanese patients with melanoma." J. Immunother.19. 428-432 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kageshita T.: "Molecular genetic analysis of HLA class II alleles in Japanese patients with melanoma." Tissue Antigens.49. 466-470 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hicklin DJ.: "Beta 2-microglobulin gene mutations in human melanoma cells : Molecular characterization and implications for immune surveillance." Melanoma Res.7. 67-74 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kageshita T.: "Differential expression of MART-1 in primary and metastatic melanoma lesions." J. Immunother.20. 460-465 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Dellaratta D.: "Characterization of rabbit antisera elicited with human LMP2- and LMP2- specific peptides and recombinant proteins." Tissue Antigens.50. 567-575 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Federico Garrido: "HLA : Genetic diversity of HLA functional and medical implication." Dominique Charron, 867 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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