Biochemical and Behavioral Correlates of IFN Response

描述(由申请人提供)： 干扰素是唯一被批准的治疗丙型肝炎病毒感染的药物。然而，与干扰素治疗相关的副作用是对丙型肝炎患者进行适当治疗的主要障碍，经常导致停用干扰素治疗。据推测，干扰素诱导的抑郁和抗病毒作用的共同机制。干扰素的两种抗病毒机制，1)激活诱导型一氧化氮合酶(INOS)和2)诱导吲哚胺2，3-双加氧酶(耗尽色氨酸)，涉及的机制也被假设为导致抑郁症。为了实现这笔赠款的目标，将追求三个具体目标：1)确定血浆亚硝酸盐、色氨酸和5-羟色胺水平与干扰素治疗反应和抑郁症状的关系；2)确定iNOS抑制剂和5-羟色胺能抗抑郁剂对T细胞对丙型肝炎病毒衍生抗原的增殖反应的影响；以及3)评估抗抑郁剂治疗对干扰素诱导的生化和治疗效果的影响。这一结果将有助于了解丙型肝炎病毒中重要的干扰素机制，并有助于了解伴随细胞因子升高的抑郁症状。

DESCRIPTION (provided by applicant): Interferon-a (IFN) is the only approved medication for hepatitis C viral (HCV) infection. However, side effects associated with IFN therapy represent a major obstacle to adequate treatment for patients with HCV, often resulting in the discontinuation IFN therapy. It is hypothesized that common mechanisms contribute to IFN-induced depression and antiviral effects. Two of IFN's antiviral mechanisms, 1) activation of inducible nitric oxide synthase (iNOS) and 2) induction of indoleamine 2,3-dioxygenase, which depletes tryptophan, involve mechanisms also hypothesized to cause depression. To accomplish the objectives of this grant, three specific aims will be pursued: 1) determine how plasma nitrite, tryptophan, and serotonin levels relate to IFN therapeutic response and depressive symptoms; 2) identify the effects of iNOS inhibition and serotonergic antidepressants on the proliferative response of T cells to HCV-derived antigens; and 3) evaluate antidepressant treatment on IFN-induced biochemical and therapeutic effects. Results will contribute to knowledge of IFN mechanisms that are important in HCV and in understanding depressive symptoms accompanying medical conditions where cytokines are elevated.