ANALYSIS OF MELANOMA IDIOTYPE NETWORK AND IT'S APPLICATION FOR VACCINE THERAPY.

黑色素瘤独特型网络分析及其在疫苗治疗中的应用。

• 批准号: 07670952
• 负责人: KAGESHITA Toshiro
• 金额: $ 1.47万
• 依托单位: KUMAMOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670952/
• 关键词: MELANOMA; HLA CLASS I; IDIOTYPE NETWORK; ANTI-IDIOTYPIC MONOCLONAL ANTIBODY; HLA class1

(1) Immunohistochemical analysis of idiotype network in melanomaThe mouse anti-id mAb MK2-23 bears the internal image of the antigenic determinant defined by anti-HMW-MAA mAb 763.74.8 HMW-MAA binding anti-anti-id Mabs elicited with mAb MK2-23 were characterized in their reactivity with a large panel of surgically removed benign and malignant melanocytic tumors. The 8 anti-anti-id mAbs displayd subtle differences in their immunoperoxidase staining of both benign and malignant tumors. The diversity in the fine specificity of the 8 anti-anti-id mAbs is likely to reflect the few somatic mutations which occur in the amino-acid sequence of the variable regions of their heavy and light chains in the course of the immune response to mAb MK2-23. The reactivity patterns of the 8 anti-anti-id mAbs with the tissue substrates are similar, although not superimposable upon that of the anti-HMW-MAA mAb 763.74 elicited with melanoma cells. This defference may reflect the imperfect mimicry by anti-id mA … More b MK2-23 of the antigenic determinant defined by anti-HMW-MAA mAb 763.74.Moreover the amino-acid sequences of 8 anti-anti-id mAbs were compared with that of anti-HMW-MAA mAb 763.74.80-95% and 85-100% homology were seen in the amino-acid sequence of the variable regions of their heavy and light chains, respectively. The highest homology was found in CDR1 and lowest in CDR3.(2) Production of anti-melanoma antibodies with anti-Id mAbAdministration of anti-Id mAb elicites anti-anti-Id mAb reacting with human melanoma cells. For the improvement of this efficacy, administration with adjuvant of anti-Id mAb MK2-23 conjugated to a carrier induces more efficiently to anti-anti-Id antibodies reacting with human melanoma cells. Moreover, F (ab') 2 fragment and chimeric mAb MK2-23 were found to reduce the anti-mouse antibodies in rabbit, which may cause the unfaborable side effect.(3) Mechanism of loss of HLA class I in melanoma lesionsThe aim of this study was to investigate the expression of HLA Class 1 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 1 allospecificities. These results indicate that the frequency of abnormalities in HLA Class 1 antigen 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. Less

（1）Melanomathe小鼠抗ID MAB MK2-23中特殊型网络的免疫组织化学分析具有由抗HMW-MAA MAB 763.74.8 HMW-MAA确定的抗原抗原的内部图像黑素细胞肿瘤。 8个抗Anti-ID MAB在良性和恶性肿瘤的免疫过氧化物酶染色方面表现出细微的差异。 8抗Anti-ID mAb的精细特异性的多样性可能反映出其重链和轻度链的可变区域的氨基酸序列中发生的少量体细胞突变，这是对MAB MK2-23的免疫响应。 8个抗Anti-ID mAb与组织底物的反应性模式相似，尽管在抗HMW-MAA MAB 763.74的抗HMW-MAA MAB 763.74上不可叠加。这种下降可能反映了抗ID MA的不完善的模拟……更多的B MK2-23是由抗HMW-MAA MAB定义定义的抗原抗原剂763.74。与抗HMW-MAA MAB 763.74.80-95-195--95--95-100％的Amino-anti-ID MAB的氨基酸序列相比他们沉重和轻链的区域。在CDR1中发现了最高的同源性，在CDR3中最低。（2）抗ID Mabadmination的抗ID MABABABICITS抗体抗体抗体的产生，抗ID MAB弹性抗体抗Anti-ID MAB与人类黑色素瘤细胞反应。为了提高这种效率，通过调整抗ID MAB MK2-23的施用与载体相结合，对与人黑色素瘤细胞反应的抗Anti-ID抗体更有效地影响。此外，发现F（ab'）2片段和嵌合MAB MK2-23可减少兔子中的抗小鼠抗体，这可能会导致不可固定的副作用。（3）黑色素瘤病变中HLA I类损失的机制，这项研究的目的是研究1类抗原在墨兰氏菌中的HLA 1抗原的表达。在此末端，在免疫过氧化物酶反应中用单克隆抗体（MAB）染色了32个原发性病变和11个转移性病变。将黑色素瘤细胞染色的强度与肿瘤巢周围的角质形成细胞的染色强度进行了比较。使用常规淋巴细胞毒性测定法确定了患者的HLA表型。大约20％的原发性和约50％的转移性病变未染色或用MAB降低的强度染色或单态特异性抗原确定剂。此外，大约40％的原发性病变和大约60％的转移性病变没有染色或用低强度染色，通过mAb到HLA 1类同种特异性。这些结果表明，HLA 1类抗原表达中异常的频率在黑色素瘤病变中很高。这些异常可能会对基于T细胞的免疫疗法产生负面影响，因为它们为黑色素瘤细胞提供了一种机制，可以摆脱细胞毒性T细胞破坏。较少的

项目成果

Nakayama J,Kageshita T,Nakashima M,Tsujisaki M,Imai K,Hori Y.: "Increase in shedding of intercellular adhesion molecule-1 in human malignant melanoma cell lines treated with hyperthermia in vitro." Pigment Cell Res.9. 154-158 (1996)

Nakayama J、Kageshita T、Nakashima M、Tsujisaki M、Imai K、Hori Y.：“体外热疗处理的人恶性黑色素瘤细胞系中细胞间粘附分子 1 的脱落增加。”

影下登志郎: "TAP分子と皮膚腫瘍" 皮膚病診療. 18. 8-11 (1996)

Toshiro Kageshita：“TAP 分子和皮肤肿瘤”皮肤科诊所。18. 8-11 (1996)

Kageshita T.: "HLA class I antigens in Japanese patients with melanoma." J Immunother.19. 428-432 (1997)

Kageshita T.：“日本黑色素瘤患者的 HLA I 类抗原。”

Kageshita, T., Kimura, T., Yoshii, A., Maruo, K., Ono, T., Himeno, M.Nishimura, Y.: "Biochemical and immunohistochemical analysis of cathepsin B,H,L and D in human melanocytic tumors." Arch.Dermatol.Res.287. 266-272 (1995)

Kageshita, T.、Kimura, T.、Yoshii, A.、Maruo, K.、Ono, T.、Himeno, M.Nishimura, Y.：“人体组织蛋白酶 B、H、L 和 D 的生化和免疫组织化学分析

Hirai S,Kageshita T,Kimura T,Tsujisaki M,Imai K,Wakamatsu K,Ito S,Ono T.: "Serum levels of sICAM-1 and 5-S-Systeinyldopa as markers of melanoma progression." Melanoma Res.(in press.).

Hirai S、Kageshita T、Kimura T、Tsujisaki M、Imai K、Wakamatsu K、Ito S、Ono T.：“sICAM-1 和 5-S-Systeinyldopa 的血清水平作为黑色素瘤进展的标志物。”