EFFECT OF STROKE ON SERUM LEVELS OF CYTOKINES AND ENDOGENOUS ANTI-(ANTI-MAG A

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stroke is the leading cause of adult disability. A number of therapies are under development to improve outcome after stroke. The purpose of the current study is to collect blood in order to measure levels of certain molecules. This information will be helpful to later studies of such therapies. There are two such future therapies that will be helped by the blood drawn in the current application. The two protocols are unrelated, but are combined herein because each requires a single tube of blood from stroke patients. Thus, 2 tubes of blood will be drawn from each subject. The first aspect of this study pertains to marrow therapy of stroke, a 10 cc vial of blood will be drawn from both stroke patients and healthy controls, and the blood will be tested for 11 different molecules. The second aspect of this study pertains to an antibody-based therapy for stroke, a 3 cc vial of blood will be drawn from stroke patients only because healthy subject data are not needed, and the blood will be tested for a single molecule. For all subjects, the blood draw plus a brief interview comprises the entire, single-visit subject participation in this study. As per above, the blood draw will consist of 2 tubes containing a total of 13 cc for stroke patients, and one tube containing a total of 10 cc for healthy controls. Regarding the first aspect of this study, blood drawn for a future study of marrow-based stroke therapy, the current study will measure levels of 11 molecules in the blood. Each molecule is in some way to systemic inflammation and stroke. This marrow-based therapy has been described in greater detail in UCI HS# 2003-3040. Note that GlaxoSmithKline (GSK) has no study management or financial involvement with this part of the study. In sum, serum levels of a number of molecules change after brain injury such as stroke, and levels of other molecules change as a result of marrow transfusion. The 11 molecules to be measured in reference to the marrow-based study are known to change either post-stroke, in marrow stromal cell cultures, or with bone marrow transplantation. These are Interleukin-2 (IL-2), IL-6, IL-4, TNFa (tumor necrosis factor alpha), IL-8, VEGF (vascular endothelial growth factor), stromal-derived factor-1 (SDF-1, also known as CXCL12), IFN-g, (interferon-gamma), G-CSF (granulocyte colony stimulating factor), GM-CSF (granulocyte-macrophage colony stimulating factor), and MMP9 (matrix metalloproteinase-9). The nature of these changes has been characterized to a limited extent. Stroke induces increases in serum IL-6, TNF-a, VEGF, and IL-4. IL-2 levels are reduced after stroke, but physical therapy can increase levels of its receptor. In bone marrow transplantation, IL-2 and IFN-g may be important influences on expression of graft-versus-host disease. Both endogenous and exogenous hematopoietic growth factors, including G-CSF and GM-CSF, can have a major influence on the success of autologous bone marrow transplantation. Marrow stromal cells, the focus of ongoing clinical trials outside of UCI and of a future stroke trial at UCI, independently elaborate a number of cytokines. In some trial settings, these cells are introduced intravenously, meaning that measurement of serum levels of cytokines is potentially important to understanding treatment effects. Regarding the second aspect of this study, blood draw for a future study of an anti-body-based stroke therapy, this blood sample collection is being conducted for GSK as a UCI investigator-initiated trial. The objectives of the study pertain to a humanized monoclonal antibody (mAb) developed by GSK, GSK249320, targeted to myelin-associated glycoprotein (MAG). Anti-MAG mAb, specifically GSK249320, is being evaluated as an approach for enhancing functional recovery post stroke by increasing neuronal plasticity and regeneration. When an anti-MAG mAb is administered to the human body, it is possible that an immune reaction may be elicited. This is commonly referred to as immunogenicity. Production of anti-(anti-MAG mAb) could either directly interfere with the efficacy of the anti-MAG mAb, or indirectly mimic antigen. Unintended immune responses are a primary concern of Food and Drug Administration (FDA) when reviewing submission of a biologic Investigational New Drug application; therefore, FDA requires immunogenicity data on all protein therapeutic compounds. The immunogenicity data should be interpreted relative to data from normal subjects as well as the target disease population; therefore, the purpose of this study is to determine the basal levels of anti-(anti-MAG mAb) (i.e., anti-drug antibody) in the target disease population (stroke) without GSK249320 treatment, as part of assay validation. Age matched blood from healthy controls will not be collected in this study, as mentioned above, as these will be obtained elsewhere.