Rook G A, Hernandez-Pando R
Department of Medical Microbiology, UCL Medical School, London, England.
Immunobiology. 1994 Oct;191(4-5):478-92. doi: 10.1016/S0171-2985(11)80454-7.
The necrotising immunopathology, which is accompanied by very little mycobactericidal activity, is probably the key to the pathogenesis of tuberculosis. Conventional chemotherapy fails to correct this immunoregulatory anomaly, so the host response does little to assist the drugs in the removal of the "persister" subpopulation of bacteria. Therefore chemotherapy must be prolonged for at least 6 months, with consequent problems of cost, resistance, and compliance. If we can learn to switch off the necrotising pathway, and replace it with bactericidal mechanisms, treatment of the disease will be enormously improved and shortened. One problem is that we do not know the mechanism of cell-mediated immunity to tuberculosis in man. On the other hand, we are gaining some insights into the mechanism of the necrosis, and there are encouraging indications that it can indeed be separated from immunity, and that it can be suppressed by suitable immunotherapy. We present here some evidence that when a TH2 response is superimposed upon a pre-existing TH1 response, the resulting cell-mediated inflammatory site becomes exquisitely sensitive to cytokine-mediated damage. There is clear evidence for a TH2 component in the immune response of tuberculosis patients. This inappropriate TH1 to TH2 shift may result from subtle endocrinological changes brought about by M. tuberculosis and the response to it. Immunotherapy should aim to switch off this TH2 component.
伴有极少杀菌活性的坏死性免疫病理学可能是结核病发病机制的关键。传统化疗无法纠正这种免疫调节异常，因此宿主反应对药物清除细菌“持留”亚群的帮助不大。所以化疗必须延长至少6个月，从而带来了成本、耐药性和依从性等问题。如果我们能够学会关闭坏死途径，并用杀菌机制取而代之，那么该病的治疗将会得到极大改善并缩短疗程。一个问题是我们尚不清楚人类对结核病细胞介导免疫的机制。另一方面，我们对坏死机制有了一些了解，并且有令人鼓舞的迹象表明坏死确实可以与免疫分离，并且可以通过适当的免疫疗法加以抑制。我们在此提供一些证据，即当TH2反应叠加在预先存在的TH1反应之上时，由此产生的细胞介导的炎症部位会对细胞因子介导的损伤变得异常敏感。有明确证据表明结核病患者的免疫反应中存在TH2成分。这种不适当的从TH1向TH2的转变可能是由结核分枝杆菌及其反应引起的细微内分泌变化导致的。免疫疗法应旨在关闭这种TH2成分。
