Paganin C, Frank I, Trinchieri G
Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 1995 Sep;96(3):1677-82. doi: 10.1172/JCI118209.
HIV-infected patients are defective in their ability to produce interleukin (IL)-12 in vitro in response to pathogenic bacteria and parasites. IL-12 enhances the patient's depressed natural killer cell cytotoxic activity, peripheral blood lymphocyte production of interferon-gamma (IFN-gamma), and proliferative T cell response in vitro to recall antigens, HIV antigens, alloantigens, and mitogens. However, these effects represent short-lived responses and imply the need for chronic IL-12 therapeutic administration in the clinical setting. To identify any long-term effects of IL-12 on T cell differentiation toward Th1 cells, peripheral blood T cells from 10 HIV-infected patients at different stages of disease were cloned by limiting dilution in the presence or absence of IL-12 and tested for cytokine production in response to stimulation with anti-CD3 antibodies and phorbol diesters IL-12 present during the first 2 wk of clonal expansion determined a stable severalfold enhancement on the ability of both CD4+ and CD8+ clones to produce IFN-gamma. Because priming for high IFN-gamma production is probably the most important mechanism by which IL-12 induces generation of efficient T helper type 1 (Th1) cells, these results suggest the possibility that IL-12 treatment in vivo of HIV-infected patients may stimulate a protective Th1 response against opportunistic pathogens and possibly HIV itself.
HIV感染患者在体外对病原菌和寄生虫产生白细胞介素（IL）-12的能力存在缺陷。IL-12可增强患者体内自然杀伤细胞的细胞毒性活性、外周血淋巴细胞产生干扰素-γ（IFN-γ）的能力，以及体外增殖性T细胞对回忆抗原、HIV抗原、同种异体抗原和丝裂原的反应。然而，这些效应只是短期反应，这意味着在临床环境中需要长期给予IL-12进行治疗。为了确定IL-12对T细胞向Th1细胞分化的任何长期影响，通过有限稀释法对10例处于不同疾病阶段的HIV感染患者的外周血T细胞进行克隆，克隆过程中分别添加或不添加IL-12，然后检测这些T细胞在受到抗CD3抗体和佛波酯刺激后产生细胞因子的情况。在克隆扩增的前2周添加IL-12，可使CD4+和CD8+克隆产生IFN-γ的能力稳定增强数倍。由于引发高IFN-γ产生可能是IL-12诱导产生高效1型辅助性T（Th1）细胞的最重要机制，因此这些结果提示，对HIV感染患者进行体内IL-12治疗可能会刺激机体产生针对机会性病原体以及可能针对HIV本身的保护性Th1反应。
