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THE MECHANISM AND IMPACT OF EARLY POST-TRANSPLANT INFLAMMATION ON THE ACTIVATION STATE, DOWN-STREAM T LYMPHOCYTE INFILTRATION, AND ESTABLISHMENT OF PROLONGED SURVIVAL OF AN ALLOGRAFT WITH CO-STIMULATION BLOCKADE THERAPY

El-Sawy, Tarek
http://rave.ohiolink.edu/etdc/view?acc_num=case1087393648

Abstract Details

2004, Doctor of Philosophy, Case Western Reserve University, Pathology.
Rejection of transplanted organs remains a significant obstacle to the long-term treatment of end-stage organ disease. Acute rejection of allografts is mediated by alloantigen-specific T cells that respond to inflammatory stimuli and infiltrate the graft where they are activated to express immune functions that mediate graft tissue destruction. A major factor directing the recruitment of T cells and other leukocytes into grafts is the production of chemoattractant cytokines, chemokines. The surgical tissue trauma and ischemia/reperfusion injury imposed on grafts induce a set of early chemokines. These early chemokines direct leukocytes without specificity for alloantigen to the graft and these cells establish inflammatory foci within the graft vasculature. Later chemokines, produced by the graft and by the early infiltrating leukocytes, then recruit alloantigen-primed T cells into the graft. The goal of this project was to define the mechanism of early inflammatory events and test their role on down stream T cell infiltration and efficacy of inhibiting T cell development with co-stimulatory blockade therapy. First, the results define an allo-immune mechanism that occurs prior to allo-specific priming and yet regulates the early inflammatory response in both duration and magnitude. Specifically, the inflammatory response was shown to be extended in duration and amplified in magnitude in cardiac allografts in comparison to syngeneic control grafts, although early chemokine levels were equivalent. This response was shown to be dependent on CD8+ T cells and IFN-? in vivo. In vitro experiments demonstrated allo-recognition and IFN-? production by CD8+ CD62Llow T cells when co-cultured with an allogeneic endothelial cell line, collectively indicating an early immune response mediated by CD8+ CD62Llow T cells (memory phenotype) to allogeneic tissues that amplifies the inflammatory response and results in increased tissue necrosis. The second result defines the role of CXCR2, a chemokine receptor expressed on PMNs, on the establishment of an intra-graft inflammatory state post-reperfusion and tests its impact on the efficacy of co-stimulatory blockade. Antagonism of CXCR2 was found to delay PMN infiltration and the attenuate inflammation associated cytokines and chemokines post-reperfusion. This attenuation delayed rejection by inhibiting the ability of allo-specifically primed lymphocytes to traffic to and infiltrate allografts. More importantly, short-term combination therapy consisting of PMN antagonism and anti-CD40L mAbs prolonged the survival of complete MHC mismatched cardiac allograft beyond 100 days, indicating a critical role of early PMN mediated inflammation at early times post-transplant on subsequent T cell infiltration and the efficacy of co-stimulatory blockade therapies.
Robert Fairchild (Advisor)
185 p.
transplantation; inflammation

Recommended Citations

Citations

  • El-Sawy, T. (2004). THE MECHANISM AND IMPACT OF EARLY POST-TRANSPLANT INFLAMMATION ON THE ACTIVATION STATE, DOWN-STREAM T LYMPHOCYTE INFILTRATION, AND ESTABLISHMENT OF PROLONGED SURVIVAL OF AN ALLOGRAFT WITH CO-STIMULATION BLOCKADE THERAPY [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1087393648

    APA Style (7th edition)

  • El-Sawy, Tarek. THE MECHANISM AND IMPACT OF EARLY POST-TRANSPLANT INFLAMMATION ON THE ACTIVATION STATE, DOWN-STREAM T LYMPHOCYTE INFILTRATION, AND ESTABLISHMENT OF PROLONGED SURVIVAL OF AN ALLOGRAFT WITH CO-STIMULATION BLOCKADE THERAPY. 2004. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1087393648.

    MLA Style (8th edition)

  • El-Sawy, Tarek. "THE MECHANISM AND IMPACT OF EARLY POST-TRANSPLANT INFLAMMATION ON THE ACTIVATION STATE, DOWN-STREAM T LYMPHOCYTE INFILTRATION, AND ESTABLISHMENT OF PROLONGED SURVIVAL OF AN ALLOGRAFT WITH CO-STIMULATION BLOCKADE THERAPY." Doctoral dissertation, Case Western Reserve University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=case1087393648

    Chicago Manual of Style (17th edition)

case1087393648
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© 2004, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.