Whary Mark T, Fox James G
Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 16-825A, Cambridge, MA 02139, USA.
Curr Top Med Chem. 2004;4(5):531-8. doi: 10.2174/1568026043451276.
Epidemiologic evidence strongly suggests that improved standards of living are associated with an increased incidence of immune system-mediated disease. Allergy, autoimmunity, and within the focus of our laboratory, idiopathic inflammatory bowel disease, most notably Crohn's disease and ulcerative colitis, and progression of chronic gastritis to gastric cancer, are all mediated by proinflammatory immune responses induced by known or unknown antigens. A popular theory, known as the 'hygiene hypothesis' (1), suggests that improved health standards achieved through sanitation and vaccination, may in part be responsible for the apparent increase in immune system-mediated disease due to decreasing microbial and parasitic infections in humans, particularly in children. As antigenic exposure of children to infectious agents, especially parasites, has rapidly decreased, it is suspected that normally protective counter-regulatory Th2-type immune responses fail to develop, increasing the risk for aberrant pro-inflammatory responses in otherwise genetically pre-disposed individuals. This hypothesis has stimulated significant interest in development of animal models of Th1- and Th2-mediated disease to test this paradigm. This review illustrates some of the exciting evidence that Th1-mediated pathology in mouse models of helicobacter disease and diabetes is ameliorated by concurrent anti-inflammatory Th2 responses to parasite antigens and that initial application of these principles is benefiting human patients. The results from developing animal models of human disease not only support the hygiene hypothesis but also have led to novel therapies using parasite antigens to stimulate anti-inflammatory Th2-type responses to restore homeostasis in patients with aberrant Th1-type immune-mediated disease.
流行病学证据有力地表明，生活水平的提高与免疫系统介导疾病的发病率增加有关。过敏、自身免疫，以及在我们实验室的研究重点中，特发性炎症性肠病，最显著的是克罗恩病和溃疡性结肠炎，还有慢性胃炎发展为胃癌，均由已知或未知抗原诱导的促炎性免疫反应介导。一种流行的理论，即“卫生假说”(1)，认为通过卫生设施和疫苗接种实现的健康标准提高，可能部分导致了免疫系统介导疾病明显增加，原因是人类尤其是儿童的微生物和寄生虫感染减少。由于儿童接触感染因子，尤其是寄生虫的抗原暴露迅速减少，人们怀疑正常情况下起保护作用的反调节性Th2型免疫反应无法发育，从而增加了在其他方面有遗传易感性的个体中出现异常促炎反应的风险。这一假说激发了人们对开发Th1和Th2介导疾病动物模型以验证这一模式的浓厚兴趣。这篇综述阐述了一些令人兴奋的证据，即在幽门螺杆菌疾病和糖尿病小鼠模型中，Th1介导的病理变化会因同时对寄生虫抗原产生的抗炎性Th2反应而得到改善，并且这些原理的初步应用正在使人类患者受益。开发人类疾病动物模型的结果不仅支持了卫生假说，还带来了使用寄生虫抗原刺激抗炎性Th2型反应以恢复Th1型免疫介导疾病异常患者体内稳态的新疗法。
