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Analysis of Immune Pathways Which Jeopardize Long-Term Pancreatic Islet Allograft Survival in the Liver

Lunsford, Keri Elizabeth
http://rave.ohiolink.edu/etdc/view?acc_num=osu1117561893

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Medical Science.
Type I Diabetes Mellitus results from autoimmune destruction of insulin-producing pancreatic islet beta cells, leading to loss of normal glucose homeostasis. Transplantation of functional pancreatic islets is a potential cure for type I diabetes. Despite recent clinical advances, application is limited due to progressive functional deterioration late after transplantation. Causes of late islet allograft dysfunction are unknown but may represent undiagnosed immunologic damage to islets. Heterotopic islet transplantation to the liver has yielded the best clinical outcomes. However, the liver is a metabolically and immunologically active organ, and experimental islet transplant studies have not historically accounted for potential effects of this immune locale on islet allograft survival and function. This dissertation research was designed to test the hypothesis that late loss of islet allograft function is due to immunologic barriers, which arise due to the activation of immune responses particular to the microenvironment of the liver. The goals of these studies were: (1) to design a clinically relevant experimental model of pancreatic islet transplantation, (2) to determine the influence of immune locale on acute alloimmune responses elicited by allogeneic islets, (3) to analyze the susceptibility of islet allografts to late immune damage following successful engraftment, and (4) to determine the utility of peripheral immune monitoring to predict transplant outcome. A clinically relevant model of intrahepatic islet transplantation was developed and was validated both functionally and histologically. Transplantation of islets to the liver neither altered the phenotype of acute rejection nor prevented induction of long-term islet acceptance. Development of a model for late allospecific immune activation (by sequential donor-matched allogeneic hepatocyte transplantation) demonstrated that islets remain vulnerable to damage by activation of local, but not peripheral, alloimmune responses. Late immune damage results from local activation of (CD4-independent) CD8+ T cell responses. However, novel immunotherapy targeting both CD4-dependent and CD8-dependent immune responses protects islets from late immune damage. Finally, peripheral monitoring to detect activation or suppression of donor-reactive humoral (alloantibody) and cell-mediated (DTH and in vivo allospecific cytotoxicity) immune responses predicted the immune status of islet allografts in vivo.
Ginny Bumgardner (Advisor)
400 p.
Health Sciences, Immunology
Pancreatic islets; Transplantation; Transplant Immunobiology; Late allograft loss; Liver Microenvironment; CD4+ T cells; CD8+ Tcells; Acute allograft rejection; Alloantibody; Delayed Type Hypersensitivity; Cytotoxicity; Local inflammatory responses

Recommended Citations

Citations

  • Lunsford, K. E. (2005). Analysis of Immune Pathways Which Jeopardize Long-Term Pancreatic Islet Allograft Survival in the Liver [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1117561893

    APA Style (7th edition)

  • Lunsford, Keri. Analysis of Immune Pathways Which Jeopardize Long-Term Pancreatic Islet Allograft Survival in the Liver. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1117561893.

    MLA Style (8th edition)

  • Lunsford, Keri. "Analysis of Immune Pathways Which Jeopardize Long-Term Pancreatic Islet Allograft Survival in the Liver." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1117561893

    Chicago Manual of Style (17th edition)

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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.