BIOLOGICAL EFFECTS OF RHIL-12

本申请中提出的研究将探讨几个问题 关于重组白细胞介素-12（rhIL-12）在 晚期癌症患者。具体目标之一是 阐明了预先注射rhIL-12似乎 使患者对这种细胞因子的毒性作用脱敏。研究 包括Scatchard分析，以评估IL-12 体外诱导的受体表达和MAPK活性的测量 与IL-12联合使用，以评估 IL-12受体几项拟议的研究涉及各种 膜相关的TNF家族成员，如Fas配体和CD 4 O- L，其可能表达于某些T细胞群体上， 对rhIL-12给药的反应。的生物学效应 这些分子，无论是在细胞表面还是进入血浆， 与TNF的那些基本上重叠，并且它们可能 可能在rhIL-12诱导的肿瘤消退或毒性中起作用 治疗IL-12是IFN-γ合成的有效诱导剂。我们的一 建议的研究包括通过RT-PCR对细胞因子进行详细分析， 由从接受rhIL-12的患者分离的TIL表达的基因。 最后，我们的一些研究集中在IL-1 2的作用上， 在T细胞中的活化诱导的细胞凋亡。这是一 CD 4 + T细胞群体逐渐增加的机制 减少感染艾滋病毒的患者，也可能影响 肿瘤浸润物内某些淋巴细胞的活力。IL-1 2 已经报道抑制活化或Fas介导的细胞凋亡， 本申请的目的之一是观察这种效应是否 在体内是可证实的。

The studies proposed in this application will explore several issues pertinent to the use of recombinant Interleukin-12 (rhIL-12) in patients with advanced cancer. One of the specific objectives is to clarify the mechanism by which a prior injection of rhIL-12 appears to desensitize patients to the toxic effects of this cytokine. The studies relating to this goal include Scatchard analyses to assess IL-12 receptor expression and measurements of MAPK activity induced in vitro with IL-12 to assess the integrity of signaling pathways downstream of the IL-12 receptor. Several proposed studies deal with various membrane-associated TNF family members such as the fas ligand and CD4O- L which are likely to be expressed on certain T cell populations in response to the administration of rhIL-12. The biological effects of these molecules, either on the cell surface or shed into the plasma, overlap substantially with those of TNF and it is possible that they may play a role in the tumor regression or toxicity induced by rhIL-12 treatment. IL-12 is a potent inducer of IFN-gamma synthesis. One of our proposed studies involves a detailed analysis by RT-PCR of the cytokine genes expressed by TIL isolated from patients receiving rhlL-I 2. Finally, several of our studies are focused on the effects of IL-I 2 administration on activation-induced apoptosis in T cells. This is one of the mechanisms by which the CD4+ T cells population is progressively diminished in patients infected with HIV and may also affect the viability of certain lymphoid cells within tumor infiltrates. IL-I 2 has been reported to inhibit activation- or fas-mediated apoptosis in vitro and one of the goals of this application is to see if this effect is demonstrable in vivo.