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Dissertation HsiaohsuanKuo OhioLink.pdf (14.1 MB)

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Early Responses in Antibody-Mediated Rejection of Vascularized Organ Transplants

Kuo, Hsiao-Hsuan
http://rave.ohiolink.edu/etdc/view?acc_num=csu1415091284

Abstract Details

2014, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
Organ transplantation remains to be the only solution for end stage organ failure. However, the immune system of transplant recipients can recognize the donor tissues as foreign and start immune responses targeting the grafts. This process will lead to loss of function and rejection of the transplants. Different forms of rejection can be classified based on the major component of the immune responses: cellular rejection (cell-mediated rejection) and humoral rejection (antibody-mediated rejection). In cell-mediated rejection, grafts are destroyed by allo-reactive CD4+ and CD8+ T lymphocytes, whereas antibody-mediated rejection is initiated by pre-existing or de novo antibodies to the graft produced by B lymphocytes. Current immunosuppressive drugs are able to effectively inhibit cell-mediated rejection. However, options for treating antibody-mediated rejection are limited and not very successful due to incomplete knowledge of factors involved in antibody-mediated rejection development. We devised a model of vascularized organ transplantation to elucidate the initial stages of antibody-mediated rejection. Complete MHC mismatched kidneys or hearts were allografted to immunodeficient mice. After perioperative inflammation subsided, donor specific alloantibodies to MHC class I antigens were passively transferred to the recipients. Within 1 hour after a single transfer of antibodies, a complement split product, C4d, was deposited diffusely on capillaries, and von Willebrand factor was released from endothelial cells and coated intravascular platelet aggregates. Platelet transported molecules (Platelet Factor 4 and serotonin) accumulated in the graft at 100 to 1000 fold higher concentrations compared with other inflammatory molecules (IL-1ß, MCP-1, MIP-1a and RANTES). Activated platelets which expressed P-selectin interacted with endothelial protrusions and infiltrating macrophages. In the kidney transplant model, the inflammatory changes were accompanied by increased levels of acute renal injury markers (IL-18, NGAL, and clusterin). When alloantibodies were transferred repeatedly for 1 week to replicate a more sustained alloantibody response, increased Mac2 positive macrophages localized to the grafts. Platelet depletion treatment by CD42b antibody 1 hr prior to alloantibody transfer decreased platelet mediators and the accumulation of macrophages. A trend of decreased acute renal injury markers compared with control groups was also observed. Our findings indicate that platelets are one of the components in the initial stage of antibody-mediated rejection. Platelets augment early inflammatory responses in antibody-mediated rejection, and selective inhibition of platelets may be beneficial for graft survival. Additionally, levels of platelet derived mediators may be markers of antibody-mediated rejection.
William Baldwin, PhD (Advisor)
Cornelia Bergmann, PhD (Committee Member)
Roman Kondratov, PhD (Committee Member)
Christine Moravec, PhD (Committee Member)
Thomas McIntyre, PhD (Committee Member)
Carol De La Motte, PhD (Committee Member)
Biomedical Research; Immunology

Recommended Citations

Citations

  • Kuo, H.-H. (2014). Early Responses in Antibody-Mediated Rejection of Vascularized Organ Transplants [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1415091284

    APA Style (7th edition)

  • Kuo, Hsiao-Hsuan. Early Responses in Antibody-Mediated Rejection of Vascularized Organ Transplants. 2014. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1415091284.

    MLA Style (8th edition)

  • Kuo, Hsiao-Hsuan. "Early Responses in Antibody-Mediated Rejection of Vascularized Organ Transplants." Doctoral dissertation, Cleveland State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1415091284

    Chicago Manual of Style (17th edition)

csu1415091284
425
© 2014, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.