Johnson B J, Ress S R, Willcox P, Pati B P, Lorgat F, Stead P, Saha R, Lukey P, Laochumroonvorapong P, Corral L
Laboratory of Cellular Physiology and Immunology, Rockefeller University, New York, NY 10021, USA.
Cytokines Mol Ther. 1995 Sep;1(3):185-96.
The immune response to infection with M. tuberculosis depends on cytokine activation of effector cells. We therefore conducted a pilot study of recombinant human interleukin-2 (rhuIL-2) as an adjunct to multidrug therapy (MDT) to evaluate the safety of this approach and to determine whether IL-2 can enhance the cellular immune response in patients with pulmonary tuberculosis (TB). Patients included in this study presented with a wide range of extent and duration of infection, and were grouped into three categories for data analysis: (1) patients with newly diagnosed, acute-stage TB who were just beginning MDT; (2) patients who had received a minimum of 45 days MDT before the start of the study and who had responded to treatment; and (3) patients with multidrug-resistant (MDR) TB who had been on MDT for at least seven months without apparent beneficial clinical response. Twenty patients received 30 days of twice-daily intradermal injections of 12.5 micrograms of IL-2. Patients from all three groups showed improvement of clinical symptoms over the 30-day period of treatment with IL-2 and MDT. Results of direct smear for acid fast bacilli (AFB) demonstrated conversion to sputum-negative following IL-2 and MDT treatment in all newly diagnosed patients and in 5/7 MDR TB patients. (The size of the skin test response to purified protein derivative (PPD) of tuberculin increased during the 30-day IL-2 adjunctive therapy in newly diagnosed patients, but decreased or disappeared in the other two groups of treated patients.) Assays in vitro for phenotype distribution, natural killer (NK) cell activity, frequency of cells proliferating in response to exogenous IL-2, and antigen-induced blastogenesis demonstrated systemic responses to intradermally administered rhuIL-2. Levels of interferon-gamma (IFN-gamma) in plasma, peripheral blood mononuclear cell (PBMC) IFN-gamma mRNA and IFN-gamma mRNA in biopsy of site of skin test response to purified protein derivative (PPD) were highest in those patients with the most acute symptoms at the beginning of the study, and decreased during rhuIL-2 and MDT. IL-2 immunotherapy did not modify levels of mRNA expression for other cytokines. Patients receiving IL-2 did not experience clinical deterioration or significant side effects. These results suggest that IL-2 administration in combination with conventional MDT is safe and may potentiate the antimicrobial cellular immune response to TB.
对结核分枝杆菌感染的免疫反应取决于效应细胞的细胞因子激活。因此，我们开展了一项关于重组人白细胞介素-2（rhuIL-2）作为多药治疗（MDT）辅助手段的初步研究，以评估该方法的安全性，并确定IL-2是否能增强肺结核（TB）患者的细胞免疫反应。本研究纳入的患者感染程度和持续时间各不相同，为进行数据分析分为三类：（1）新诊断的急性期TB患者，刚开始接受MDT；（2）在研究开始前已接受至少45天MDT且治疗有反应的患者；（3）耐多药（MDR）TB患者，已接受MDT至少七个月但无明显有益临床反应。20名患者接受了30天每日两次、每次12.5微克IL-2的皮内注射。所有三组患者在接受IL-2和MDT治疗的30天期间临床症状均有改善。抗酸杆菌（AFB）直接涂片结果显示，所有新诊断患者以及5/7的MDR TB患者在接受IL-2和MDT治疗后痰菌转阴。（新诊断患者在30天的IL-2辅助治疗期间对结核菌素纯蛋白衍生物（PPD）的皮肤试验反应大小增加，但在其他两组接受治疗的患者中减小或消失。）体外对表型分布、自然杀伤（NK）细胞活性、对外源性IL-2反应增殖的细胞频率以及抗原诱导的母细胞化的检测表明，对皮内注射的rhuIL-2有全身反应。血浆中干扰素-γ（IFN-γ）水平、外周血单个核细胞（PBMC）IFN-γ mRNA以及对结核菌素纯蛋白衍生物（PPD）皮肤试验反应部位活检中的IFN-γ mRNA在研究开始时症状最急性的患者中最高，在rhuIL-2和MDT治疗期间下降。IL-2免疫治疗未改变其他细胞因子的mRNA表达水平。接受IL-2的患者未出现临床恶化或明显副作用。这些结果表明，IL-2与传统MDT联合使用是安全的，可能会增强对TB的抗微生物细胞免疫反应。
