Brain death (BD) and ischemia reperfusion injury (IRI) are unavoidable consequences of heart transplantation. Brain death produces profound physiologic derangements and the systemic effects of this central injury, although little studied, are known to contribute to peripheral organ ischemia, the upregulation of adhesion molecules, cytokine expression and leukocyte accumulation within the donor heart. Brain death induced inflammation in the donor also renders the heart more susceptible to IRI in the recipient, and there is evidence to indicate that both of these injurious events have negative long-term consequences with regard to allograft survival. Our working hypothesis is that complement plays a central role in causing myocardial BD- induced inflammation and injury, and enhances IRI in the recipient. We propose that a complement inhibitory strategy applied to the donor (in addition to the recipient) will provide protection from inflammation and injury, and as a consequence, will improve long-term graft survival due to decreased graft immunogenicity and host alloresponsiveness. We propose to utilize relevant mouse models to determine the role of complement in myocardial brain death induced injury (BDI) and in IRI following heart transplantation. Our investigations will focus on complement effector mechanisms and in vivo interactions between complement and P-selectin, an adhesion molecule that is strongly implicated in myocardial IRI and that is expressed in the heart following BD. We further propose to develop novel therapeutic strategies based on targeted complement inhibition and P-selectin antagonism, and to characterize the inhibitors in our newly developed mouse model of heart transplantation incorporating donor BD. We specifically propose to: 1. Determine complement effector mechanism(s) involved in myocardial injury following brain death 2. Develop and characterize novel therapeutic strategies based on P-selectin targeted complement inhibition and P-selectin antagonism and, 3. Determine the effect of anti-complement therapy in the BD donor, the recipient, or both, on the severity of myocardial IRI after heart transplantation and on the development of an alloimmune response and acute rejection of the graft. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL086576-01A1
Application #
7303997
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Desvigne-Nickens, Patrice
Project Start
2007-08-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$384,797
Indirect Cost
Name
Medical University of South Carolina
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Gelber, Shari E; Brent, Elyssa; Redecha, Patricia et al. (2015) Prevention of Defective Placentation and Pregnancy Loss by Blocking Innate Immune Pathways in a Syngeneic Model of Placental Insufficiency. J Immunol 195:1129-38
Varela, Juan Carlos; Tomlinson, Stephen (2015) Complement: an overview for the clinician. Hematol Oncol Clin North Am 29:409-27
Atkinson, Carl; Qiao, Fei; Yang, Xiaofeng et al. (2015) Targeting pathogenic postischemic self-recognition by natural IgM to protect against posttransplantation cardiac reperfusion injury. Circulation 131:1171-80
Liu, Fengming; Wu, Lin; Wu, Gongxiong et al. (2014) Targeted mouse complement inhibitor CR2-Crry protects against the development of atherosclerosis in mice. Atherosclerosis 234:237-43
Marshall, Keely M; He, Songqing; Zhong, Zhi et al. (2014) Dissecting the complement pathway in hepatic injury and regeneration with a novel protective strategy. J Exp Med 211:1793-805
Holers, V Michael; Rohrer, Bärbel; Tomlinson, Stephen (2013) CR2-mediated targeting of complement inhibitors: bench-to-bedside using a novel strategy for site-specific complement modulation. Adv Exp Med Biol 735:137-54
Atkinson, Carl; Floerchinger, Bernhard; Qiao, Fei et al. (2013) Donor brain death exacerbates complement-dependent ischemia/reperfusion injury in transplanted hearts. Circulation 127:1290-9
Elvington, Andrew; Atkinson, Carl; Kulik, Liudmila et al. (2012) Pathogenic natural antibodies propagate cerebral injury following ischemic stroke in mice. J Immunol 188:1460-8
Elvington, Andrew; Atkinson, Carl; Zhu, Hong et al. (2012) The alternative complement pathway propagates inflammation and injury in murine ischemic stroke. J Immunol 189:4640-7
Sekine, Hideharu; Kinser, Ting Ting Hsieh; Qiao, Fei et al. (2011) The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. Arthritis Rheum 63:1076-85

Showing the most recent 10 out of 17 publications