CNS antigen sensitization in stroke.

University Of Washington, Seattle WA

Investigators

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Abstract

DESCRIPTION (provided by applicant): The primary aims of this study are to determine how many patients become sensitized (develop a Th1 immune response) to brain antigens after stroke and whether infection in the immediate post-stroke period increases the risk of becoming sensitized to those antigens. The rationale for this study is based on the fact that the integrity of the blood-brain barrier is breached in stroke; cells of the immune system thus encounter novel central nervous system (CMS) antigens in both the brain and in the systemic circulation. This encounter may result in an immune response to those antigens and the microenvironment at the site of encounter determines the nature of the immune response generated. For instance, a systemic inflammatory response, such as occurs with infection, could induce the expression of costimulatory molecules and promote sensitization of lymphocytes (Th1 immune response) to brain antigens. In animal models of stroke, lymphocytes sensitized to CMS antigens contribute to cerebral injury and manipulation of the immune response improves outcome from stroke. Similar manipulation of the immune response could provide a therapeutic target for clinical intervention. To date, however, attempts at manipulating the immune response in patients with stroke have produced either no clinical benefit or even harm. Thus, prior to conducting further trials of immune modulation in clinical stroke, the nature and the consequences of the post-ischemic immune response need to be understood. For the purposes of this study, antigen-specific immune responses to brain antigens will be evaluated serially over the course of 1 year in patients who present with acute ischemic stroke; the type of immune response, Th1 versus Th2/Th3, will be compared between patients who develop infection in the immediate post-stroke period and those who do not. The effect of stroke subtype and endogenous immunomodulatory responses on the likelihood of becoming sensitized to brain antigens will also be assessed. Progression of white matter disease and brain atrophy, as detected by magnetic resonance imaging, will be used as a surrogate measure of the pathologic consequences of a Th1 response. Data derived from this study will be used to plan future trials of immunomodulation in patients with stroke.