MHC GENE PRODUCTS IN PROTECTING CELLS AGAINST NK LYSIS

这项研究项目的目的是进一步证明主要的 组织相容性复合体(MHC)基因产物可保护肿瘤和正常 自然杀伤细胞(NK)和淋巴因子对细胞的杀伤作用 (IL-2)激活的杀伤细胞(LAK)。研究的目的也是为了 (I)阐明MHC基因产品提供这种能力的机制 保护，以及(Ii)确定第I类与 人类白细胞抗原II类分子(及其多态决定因素)在提供 对正常或肿瘤细胞的保护。 在这些体外研究中，人类肿瘤细胞是从淋巴和 实体肿瘤将与自体和/或 同种异体人NK和LAK细胞。类似的研究将在 正常人体细胞，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“屏蔽”这些物质来确定 使用单抗或(Fab)‘2抗体的抗原 都是最近出版的。 正常细胞(如B淋巴细胞)将被淋巴因子激活， 抗原和病毒(如EBV)。MHC产品在以下方面的作用 保护这种活化的和暴露于抗原的细胞免受自体或 然后将确定同种异体NK或LAK裂解。 在使用伽马干扰素之前，肿瘤细胞也会被激活 他们是NK或LAK溶血的靶子。改变肿瘤细胞MHC的作用 含有干扰素的产品将在这些细胞溶解物质中进行检测 实验。在涉及NK和LAK裂解的单独研究中，我们将使用 以I类基因表达不同的突变肿瘤细胞系为靶点 或II类MHC分子，以及转MHC基因组的肿瘤细胞。 裂解数据(MHC分子掩蔽前后)与 MHC抗原表达水平和结合物形成应产生更多 关于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的了解(和 也许用生物制剂治疗)和自身免疫机制。

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.