Genetic Determinants of Interleukin-10 response after infectious stimuli

白细胞介素-10是免疫防御感染的关键蛋白，是免疫反应的主要制动器。白细胞介素-10的产生减少已被认为是导致感染性休克和急性呼吸窘迫综合征等许多破坏性疾病的主要原因。白细胞介素-10的过量产生也可能非常有害，可能是许多危重病人免疫功能下降的主要原因，从而导致医院获得性感染。白细胞介素-10在重症患者中的这些潜在关键作用使其成为免疫治疗的一个有吸引力的候选靶点。然而，过去基于免疫疗法（如肿瘤坏死因子α）的试验经验告诉我们，如果我们要成功地“干扰”免疫系统，我们需要更好地预测个体免疫反应。就白细胞介素-10而言，产生的数量存在很大的个体差异，研究表明，这种差异的70%是由于遗传差异。该项目将通过确定高和低白介素-10反应的遗传标记以及这些遗传标记改变白介素-10产生的机制来建立这种遗传变异的基础。这些信息不仅使我们能够更好地针对可能需要“调整”其免疫功能的患者，而且还可能导致新的治疗靶点或治疗剂。

Interleukin-10 is a key protein in the immune defense against infection, being the principal brake for the immune response. An diminished production of interleukin-10 has been implicated as a major cause of a number of devestating medical conditions including septic shock and acute respiratory distress syndrome. An excessive production of interleukin-10 may also be very harmful, and may be the primary cause of the reduction in immune function in many critically ill patients that leads to hospital acquired infections. These potential key roles of interleukin-10 in seriously ill patients makes it an attractive candidate to target for immune therapies. However, past experience with trials of immune-based therapies such as tumor necrosis factor alpha have taught us that we need to be much better at predicting individual immune responses if we are to 'interfere' with the immune system successfully. In the case of interleukin-10 there is substantial individual variation in the amount produced, with studies suggesting up to 70% of this variation is due to genetic differences. This project will establish the basis for this genetic variation by identiying both the genetic markers of high and low interleukin-10 response and the mechanisms by which these genetic markers change interleukin-10 production. This information will not only enable us to better target patients who may need an 'adjustment' of their immune function, but may also lead to novel therapeutic targets or therapeutic agents.