Aleman M, De La Barrera S, Fink S, Finiasz M, Farina M H, Pizzariello G, Sasiain M D
ANM. Departamento Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
Scand J Immunol. 2000 Mar;51(3):262-70. doi: 10.1046/j.1365-3083.2000.00675.x.
Interleukin-12 (IL-12) is a major immunomodulatory cytokine that represents a functional bridge between the early resistance and the subsequent antigen specific adaptive immunity. TNF-alpha and IFN-gamma have an important role in the generation of hsp65 specific cytotoxic T lymphocytes (CTL) that lyse hsp65-pulsed autologous macrophages (hsp65 CTL). Since a positive feedback mechanism between TNF-alpha, IFN-gamma and IL-12 has been described, we undertook to evaluate the role of IL-12 on the hsp65 CTL generation in leprosy patients. Our results show that the presence of IL-12 during the first 24 h of the in vitro antigen stimulation amplifies the hsp65 cytotoxic response whenever both IFN-gamma and TNF-alpha are present. The addition of these three cytokines (CKs) was able to abrogate the inhibitory effect of IL-10 on hsp65 CTL in cells from paucibacillary patients (PB) but not that of IL-4 in PB and normal controls (N). Both IL-12 or anti IL-4 enhanced the cytotoxic activity in cells from multibacillary patients (MB). Anti IL-4 upregulated the binding of IFN-gamma and did not modify that of TNF-alpha so the low CTL activity could be as a result of IL-4 by a decrease of the IFN-gamma binding on MB cells. Cells from those MB patients taking thalidomide (MB-T) did neither bind IFN-gamma nor TNF-alpha even when antigen or anti-IL-4 were added, demonstrating that thalidomide inhibits either the in vitro binding or receptor expression of both TNF-alpha and IFN-gamma. Development of CD56 effector cells during the hsp65 stimulation was observed in PB and N by the addition of IL-12 plus TNF-alpha and IFN-gamma, while in MB and MB-T anti IL-4 was also required. So, the inhibitory effect of IL-4 on either production of IFN-gamma, TNF-alpha and/or IL-12 or their receptors could be the mechanism underlying the lack of the hsp65 CTL generation in cells from MB.
白细胞介素-12（IL-12）是一种主要的免疫调节细胞因子，它代表了早期抵抗力与随后的抗原特异性适应性免疫之间的功能桥梁。肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）在热休克蛋白65（hsp65）特异性细胞毒性T淋巴细胞（CTL）的产生中起重要作用，这些CTL可裂解经hsp65脉冲处理的自体巨噬细胞（hsp65 CTL）。由于已描述了TNF-α、IFN-γ和IL-12之间的正反馈机制，我们着手评估IL-12在麻风病患者hsp65 CTL产生中的作用。我们的结果表明，在体外抗原刺激的最初24小时内存在IL-12时，只要同时存在IFN-γ和TNF-α，就会增强hsp65细胞毒性反应。添加这三种细胞因子（CKs）能够消除IL-10对少菌型患者（PB）细胞中hsp65 CTL的抑制作用，但不能消除PB和正常对照（N）中IL-4的抑制作用。IL-12或抗IL-4均可增强多菌型患者（MB）细胞的细胞毒性活性。抗IL-4上调了IFN-γ的结合，而未改变TNF-α的结合，因此低CTL活性可能是由于IL-4导致MB细胞上IFN-γ结合减少所致。即使添加抗原或抗IL-4，服用沙利度胺的MB患者（MB-T）的细胞也既不结合IFN-γ也不结合TNF-α，这表明沙利度胺抑制TNF-α和IFN-γ的体外结合或受体表达。通过添加IL-12加TNF-α和IFN-γ，在PB和N中观察到hsp65刺激过程中CD56效应细胞的发育，而在MB和MB-T中还需要抗IL-4。因此，IL-4对IFN-γ、TNF-α和/或IL-12的产生或其受体的抑制作用可能是MB细胞中缺乏hsp65 CTL产生的潜在机制。
