Genetic Determinants of Interleukin-10 response after infectious stimuli

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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.