ACTIVATION OF NON MHC-RESTRICTED CYTOTOXIC LYMPHOCYTES

定义细胞毒性和其他功能的机制 NK细胞，它们的亚群或不成熟的前体细胞， 淋巴因子是了解这些细胞所起作用的先决条件 在生理和病理条件下或在收养期间， 免疫疗法结合生物反应调节剂。 我们有 定义了体外培养系统，其中成熟NK细胞，和/或 NK和T细胞亚群在外周血中以低比例存在 血液，诱导增殖，并已纯化至同质， 细胞因子，操作上称为NKSF。 NKSF是NK的有效调节剂 细胞，其作用独立于IL-2 （细胞毒性），协同作用（诱导淋巴因子产生）或 对抗其作用（增殖）。 为了定义分子 IL-2和NKSF对NK细胞作用的机制 功能，我们建议：a）识别淋巴因子和细胞毒性分子 其表达受IL-2的不同调节， NKSF并分析其诱导的分子基础 淋巴因子，B）以确定NKSF抑制 IL-2诱导的增殖。 NKSF不是NK细胞特异性的。 以限定 对NKSF敏感的白细胞亚群，我们将研究其对T细胞的影响 以及它们的一些亚群（特别是那些可被IL-2诱导以介导 MHC-非限制性细胞毒性），我们将尝试产生单克隆 NKSF受体的抗体。 我们观察到，在我们的文化体系中， 具有NK表型的细胞被诱导从耗尽的PBL增殖， 成熟NK细胞 我们的工作假设是NK细胞前体是 在这些条件下诱导分化，我们将测试这个 通过分析它们在外周血和骨骼中的存在， 骨髓 从这里提出的研究，我们希望得到新的 关于NK细胞生物学的信息，以及不同的NK细胞 淋巴因子发挥增强这些和其它细胞毒性细胞功能作用 类型

Defining the mechanisms whereby cytotoxicity and other functions of NK cells, their subpopulations or immature precursors, are modulated by lymphokines is a prerequisite to understand the role played by these cells in physiological and pathological conditions or during adoptive immunotherapy in conjunction with biological response modifiers. We have defined an in vitro culture system in which mature NK cells, and/or subpopulations of NK and T cells present in low proportion in peripheral blood, are induced to proliferate and have purified to homogeneity a novel cytokine, operationally termed NKSF. NKSF is a potent regulator of NK cells, of which it affects functions independently from IL-2 (cytotoxicity), in synergy with it (induction of lymphokine production) or antagonizing its effects (proliferation). In order to define the molecular mechanisms that contribute to the effects of IL-2 and NKSF on NK cell functions, we propose: a) to identify lymphokines and cytotoxic molecules whose expression is differentially modulated by IL-2 in comparison with NKSF and analyze the molecular basis for their induction by the two lymphokines, b) to determine the mechanism(s) by which NKSF inhibits IL-2-induced proliferation. NKSF is not NK-cell specific. To define leucocyte subsets sensitive to NKSF, we will study its effect on T cells and some of their subsets (in particular those inducible by IL-2 to mediate MHC-non restricted cytotoxicity) and we will attempt to produce monoclonal antibodies to the NKSF-receptor. We observed that, in our culture system, cells with NK phenotype are induced to proliferate from PBL depleted of mature NK cells. It is our working hypothesis that NK cell precursors are induced to differentiate in these conditions, and we will test this hypothesis by analyzing their presence both in peripheral blood and bone marrow. From the studies proposed here, we expect to derive novel information on the biology of NK cells and on the role that distinct lymphokines play to enhance functions of these and other cytotoxic cell types.