Ischemia-reperfusion injury (I/R) represents inflammatory injury to the endothelium and underlying parenchymal tissues following reperfusion of hypoxic tissues. This general syndrome is responsible for both acute and chronic injury to various tissues including the myocardium, central nervous system, hind limb andintestine. Studies in rodent models implicate the complement system as a major mediator of injury (1-3). Serum natural IgM is also critical in the induction of injury in two distinct tissues for activation of complement (3, 4). A universal mechanism that would explain these observations is that the hypoxic endothelium expresses neoantigens that specifically bind natural IgM leading to activation of the classical pathway of complement and the inflammatory response. This project will test this hypothesis in three inter-related specific aims.
The first aim will test our hypothesis that natural IgM mediates local I/R injury and that a major source is CD11b+ peritoneal B-1 cells.
This aim will include identification of B-1 cell hybridomas that secrete IgM that induce I/R injury in vivo. One hybridoma clone (CM22) expressing specific antibody has been identified and it will be further characterized in the second aim. We will uncouple IgM binding to ischemic tissues and activation of complement pathway using various genetic approaches. In the final aim, we will examine the development and regulation of B cell subsets that express ischemia-specific anti-self-antibody. The proposed study is important as it will not only provide important reagents and murine models for furthering our understanding of the etiology of ischemia reperfusion injury but hopefully lead to the identification of a therapeutic approach to intervene in this major disorder of humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
5P50GM052585-12
Application #
7551115
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
12
Fiscal Year
2006
Total Cost
$283,500
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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