Fox F E, Chernajovsky Y, Platsoucas C D
Department of Immunology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Hybridoma. 1994 Oct;13(5):343-52. doi: 10.1089/hyb.1994.13.343.
We investigated the mechanisms by which two human T-T cell hybridoma-derived suppressor factors (SFs) (designated 160 and 169) (Platsoucas et al., Hybridoma 1987;6:589; Kunicka et al., Hybridoma 1989;8:127) inhibit the proliferative response to mitogens by human peripheral blood mononuclear cells (PBMCs). Interleukin 2 (IL-2) production by human PBMCs cultured with concanavalin A or OKT3 monoclonal antibody for 12 or 36 hr in the presence of 160 or 169 SF was found to be inhibited > 80% when compared to control PBMC cultures stimulated with mitogen in the absence of SFs. This suppression of IL-2 production was not due to the SFs interfering with IL-2-induced proliferation of the IL-2-dependent murine cell clone used to determine the levels of IL-2. The proliferative responses of SF-treated PBMCs could not be restored by addition of exogenous recombinant human IL-2 (rIL-2) (1-100 U/ml). Furthermore, inhibition of the proliferative responses by the SFs could not be reversed by addition of exogenous rIL-1, rIL-2, or rIL-4 alone or in paired combinations. The expression of IL-2 receptors (TAC Ag) on concanavalin A-activated cultures at 12- or 36-hr time points was not affected by treatment with the SFs. Both the 160 and 169 hybridoma-derived SFs were found to cause the accumulation of an mRNA of 2.8 kb that hybridized with an IL-2-specific oligonucleotide probe. This 2.8-kb transcript was in addition to the expected 1.0-kb, transiently expressed IL-2 message, and it could be superinduced in the presence of cycloheximide. These results suggest that these SFs may be influencing RNA splicing pathways. These SFs appear to be useful molecules for probing the regulatory controls of lymphocyte proliferation and may constitute important physiological regulators of the immune response. In addition, they may have clinical activity for the treatment of patients that received transplants, patients with autoimmune diseases, and others.
我们研究了两种源自人T - T细胞杂交瘤的抑制因子（SFs）（命名为160和169）（普拉措卡斯等人，《杂交瘤》1987年；6:589；库尼卡等人，《杂交瘤》1989年；8:127）抑制人外周血单个核细胞（PBMCs）对丝裂原增殖反应的机制。发现在存在160或169 SF的情况下，用伴刀豆球蛋白A或OKT3单克隆抗体培养12或36小时的人PBMCs产生白细胞介素2（IL - 2）的量，与在无SFs情况下用丝裂原刺激的对照PBMC培养物相比，被抑制了80%以上。IL - 2产生的这种抑制并非由于SFs干扰用于测定IL - 2水平的依赖IL - 2的鼠细胞克隆的IL - 2诱导的增殖。添加外源性重组人IL - 2（rIL - 2）（1 - 100 U/ml）不能恢复经SF处理的PBMCs的增殖反应。此外，单独添加外源性rIL - 1、rIL - 2或rIL - 4或成对组合添加均不能逆转SFs对增殖反应的抑制。在12或36小时时间点，伴刀豆球蛋白A激活的培养物上IL - 2受体（TAC抗原）的表达不受SFs处理的影响。发现源自160和169杂交瘤的两种SFs都会导致一种与IL - 2特异性寡核苷酸探针杂交的2.8 kb mRNA的积累。这种2.8 kb转录本除了预期的1.0 kb瞬时表达的IL - 2信息外，并且在存在环己酰亚胺的情况下可被超诱导。这些结果表明这些SFs可能影响RNA剪接途径。这些SFs似乎是用于探究淋巴细胞增殖调控控制的有用分子，并且可能构成免疫反应的重要生理调节因子。此外，它们可能对接受移植的患者、自身免疫性疾病患者及其他患者具有临床治疗活性。
