Ischemia followed by reperfusion (IR), which occurs unavoidably during organ transplantation, elicits immune responses that contribute to graft dysfunction. Delineating novel, effective therapies to prevent IR injury has the potential to change clinical practice and improve patient health following organ transplantation. The goals of this project are to define the role of complement factor B (fB) in post-transplant injury, identify new mouse and human fB antagonists and begin to test them in animal models. The long term goal is to use the inhibitors to prevent allograft injury in humans. Our combined published and preliminary data demonstrate that: blocking complement activation in a donor organ prolongs allograft survival in mice; fB gene expression is increased in biopsies of heart transplantation patients compared with levels in normal heart tissue, and correlates with graft rejection grades; in a murine myocardial IR model, injury is significantly reduced in fB-/- mice; fB is significantly activated in the hearts of patients undergoing open heart surgery, i.e., experiencing surgically-induced global heart ischemia; in these patients, the levels of Bb, the activated fB fragment, correlate with the post- surgical increase of circulating cardiac troponin I, a marker of myocardia injury. Thus, fB expression and activation in donor organs are important in graft rejection.
The specific aims are: 1) To identify small peptide antagonists specific for murine and for human fB using a phage display peptide library. 2) To determine the role of fB in transplant rejection in mice and to test the efficacy of fB inhibition. We expect that the studies will identify novel fB inhibitors, provide new insight into mechanisms of IR injury and transplant rejection, and provide preclinical data to support human studies to block fB in vivo.
Ischemia/reperfusion occurs during organ transplantation and elicits immune responses contributing to graft rejection. The goals of the project are to define the role of complement factor B (fB), in graft rejection, to identify new inhibitors to mouse and human fB, and to begin to test them in animal models and human tissues.
| Chun, Nicholas; Haddadin, Ala S; Liu, Junying et al. (2017) Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury. PLoS One 12:e0179450 |
| Chun, N; Fairchild, R L; Li, Y et al. (2017) Complement Dependence of Murine Costimulatory Blockade-Resistant Cellular Cardiac Allograft Rejection. Am J Transplant 17:2810-2819 |
| Heeger, P S (2015) What's hot, what's new in basic science: report from the American Transplant Congress 2015. Am J Transplant 15:2802-7 |
| Charchaflieh, Jean; Rushbrook, Julie; Worah, Samrat et al. (2015) Activated Complement Factors as Disease Markers for Sepsis. Dis Markers 2015:382463 |
