Vanham G, Toossi Z, Hirsch C S, Wallis R S, Schwander S K, Rich E A, Ellner J J
Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium.
Tuber Lung Dis. 1997;78(3-4):145-58. doi: 10.1016/s0962-8479(97)90021-6.
Protective immunity against Mycobacterium tuberculosis (MTB) in animal models is based on cell-mediated immunity (CMI), involving bi-directional interactions between T cells and cells of the monocyte/macrophage (MO/MA) lineage. Key factors include MO-derived interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha as well as T cell derived IL-2 and interferon (IFN)-gamma. These cytokines appear particularly crucial in the induction of MA-mediated elimination of mycobacteria. Several lines of evidence indicate that similar mechanisms are operating in humans. During active pulmonary tuberculosis (PTB), signs of both immune depression and immune activation are concomitantly present. Decreased tuberculin skin test reactivity in vivo and deficient IFN-gamma production by MTB-stimulated mononuclear cells in vitro are observed. On the other hand, the serum levels of several cytokines, including TNF, and other inflammatory mediators are increased and circulating MO and T cell show phenotypic and functional evidence of in vivo activation. In this review, we will discuss the evidence for three models, which could explain this apparent paradox: 1. Stimulation of the T cell-suppressive function from MO/MA; 2. Intrinsic T cell refractoriness, possibly associated with tendency to apoptosis (programmed cell death), and 3. Compartmentalization and redistribution of immune responses to the site of disease. The opportunistic behavior of MTB during human immunodeficiency virus (HIV) infection can be explained by suppression of type-1 responses at the level of antigen-presenting cells, CD4 T cells and effector macrophages. The ominous prognostic significance of intercurrent PTB during HIV infection seems primarily due to prolonged activation of HIV replication in macrophages. Supportive immune therapy during PTB could aim at correcting the type-1 deficiency either by IFN-gamma inducers (e.g. IL-12, IL-18) or by neutralizing the suppressive cytokines transforming growth factor beta (TGF-beta) and IL-10. Alternatively, inflammatory over-activity could be reduced by neutralizing TNF. Finally, anti-apoptotic therapies (e.g. IL-15) might be considered.
动物模型中针对结核分枝杆菌（MTB）的保护性免疫基于细胞介导的免疫（CMI），涉及T细胞与单核细胞/巨噬细胞（MO/MA）谱系细胞之间的双向相互作用。关键因素包括MO衍生的白细胞介素（IL）-12和肿瘤坏死因子（TNF）-α，以及T细胞衍生的IL-2和干扰素（IFN）-γ。这些细胞因子在诱导MA介导的分枝杆菌清除中似乎尤为关键。多条证据表明，人类中也存在类似机制。在活动性肺结核（PTB）期间，免疫抑制和免疫激活的迹象同时出现。观察到体内结核菌素皮肤试验反应性降低，以及体外MTB刺激的单核细胞产生IFN-γ不足。另一方面，包括TNF在内的几种细胞因子以及其他炎症介质的血清水平升高，循环中的MO和T细胞显示出体内激活的表型和功能证据。在本综述中，我们将讨论三种模型的证据，这些证据可以解释这一明显的矛盾现象：1. MO/MA对T细胞抑制功能的刺激；2. 内在的T细胞不应性，可能与细胞凋亡（程序性细胞死亡）倾向有关；3. 免疫反应在疾病部位的分隔和重新分布。人类免疫缺陷病毒（HIV）感染期间MTB的机会性表现可以通过抗原呈递细胞、CD4 T细胞和效应巨噬细胞水平上1型反应的抑制来解释。HIV感染期间并发PTB的不良预后意义似乎主要归因于巨噬细胞中HIV复制的长期激活。PTB期间的支持性免疫治疗可以旨在通过IFN-γ诱导剂（如IL-12、IL-18）或通过中和抑制性细胞因子转化生长因子β（TGF-β）和IL-10来纠正1型缺陷。或者，可以通过中和TNF来降低炎症过度活动。最后，可以考虑抗凋亡疗法（如IL-15）。
