MHC GENE PRODUCTS IN PROTECTING CELLS AGAINST NK LYSIS

MHC 基因产品保护细胞免受 NK 裂解

• 批准号: 3194754
• 负责人: PETER LOBO
• 金额: $ 14.63万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-05-01 至 1994-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3194754
• 关键词: B lymphocyte; Epstein Barr virus; MHC class I antigen; MHC class II antigen; antibody dependent killer cell; cell mediated lymphocytolysis test; cellular oncology; cytolysis; histocompatibility antigens; human tissue; interferons; interleukin 2; leukocyte activation /transformation; major histocompatibility complex; monoclonal antibody; natural killer cells; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplastic cell; tissue /cell culture; transfection

The aim of this research project is to further document that the major histocompatibility complex (MHC) gene products can protect tumor and normal cells against cytolysis by natural killer cells (NK) and by lymphokine (interleukin2) activated killer cells (LAK). Studies will also be aimed at (i) elucidating the mechanism by which MHC gene products afford such protection, and (ii) determining the relative importance of class I vs Class II HLA molecules (and their polymorphic determinants) in affording protection to normal or tumor cells. In these in-vitro studies human tumor cells obtained form lymphoid and solid-tumor malignancies will be interacted with autologous and or allogeneic human NK and LAK cells. Similar studies will be performed on normal human cells, i.e. lymphocytes and freshly obtained (and cultured) endothelial cells. The protective role of MHC gene products on cell membranes will be primarily determined by "blocking" or "masking" these antigens with monoclonal or (Fab) '2 antibodies using techniques that we have recently published. Normal cells (e.g. B lymphocytes) will be activated with lymphokines, antigens, and with viruses (e.g. EBV). The role of MHC products in protecting such activated and antigen exposed cells against autologous or allogeneic NK or LAK lysis will then be determined. Tumor cells will also be activated with gamma-interferon prior to using them as targets in NK or LAK lysis. The effect of altering tumor cell MHC products with interferon will then be assayed in these cytolytic experiments. In separate studies involving NK and LAK lysis, we will use as targets mutant tumor cell lines that vary in their expression of Class I or II MHC molecules and also tumor cells transfected with MHC genomes. Correlating lytic data (before and after masking of MHC molecules) with level of MHC antigen expression and conjugate formation should yield more conclusive data on the role of MHC in tumor cell protection. These studies will increase our understanding on cancer immunity (and perhaps therapy with biological agents) and with autoimmune mechanisms.

本研究项目的目的是进一步证明， 组织相容性复合体（MHC）基因产物对肿瘤和正常人具有保护作用 细胞抵抗自然杀伤细胞（NK）和淋巴因子的细胞溶解 （白细胞介素2）激活的杀伤细胞（LAK）。 研究还将针对 (i)阐明了MHC基因产物提供这种功能的机制， 保护，以及（ii）确定I类与 II类HLA分子（及其多态性决定簇）在提供 保护正常或肿瘤细胞。 在这些体外研究中，人肿瘤细胞从淋巴和淋巴细胞中获得， 实体瘤恶性肿瘤将与自体和/或 同种异体人NK和LAK细胞。 类似的研究将在 正常人细胞，即淋巴细胞和新鲜获得的（和培养的） 内皮细胞 MHC基因产物对细胞的保护作用 膜将主要通过“阻断”或“掩蔽”这些 抗原与单克隆抗体或（Fab）'2抗体， 最近出版了。 正常细胞（例如B淋巴细胞）将被淋巴因子激活， 抗原和病毒（例如EBV）。 MHC产物的作用 保护这些活化的和抗原暴露的细胞免受自体或 然后测定同种异体NK或LAK溶解。 肿瘤细胞也将被激活与γ-干扰素之前，使用 它们作为NK或LAK裂解的靶点。 改变肿瘤细胞MHC的作用 然后将在这些细胞溶解性细胞中测定含有干扰素的产物， 实验 在涉及NK和LAK细胞溶解的单独研究中，我们将使用 作为靶点的突变肿瘤细胞系，其I类 或II型MHC分子以及用MHC基因组转染的肿瘤细胞。 将裂解数据（MHC分子掩蔽前后）与 MHC抗原表达水平和缀合物形成应产生更多的 MHC在肿瘤细胞保护中的作用的结论性数据。 这些研究将增加我们对癌症免疫力的了解（以及 可能用生物制剂治疗）和自身免疫机制。