Composite tissue allotransplantation

This dissertation explores three theses related to the field of composite tissue allotransplantation (CTA). CTA refers to the transplantation of connective tissues. Whereas solid organ transplantation primarily aims to restore homeostatic and often life dependent functions, CTA aims to restore tissue integrity for the purpose of reconstruction. Despite the fact that CTA was conceptualized centuries before solid organ transplantation, the latter has become standard-of-care while CTA continues to be an experimental procedure. Three main reasons can be held accountable for this lack of implementation: (1) the risk of immunosuppression, which many argue does not justify the transplantation of non-lifesaving tissues; (2) the risk of graft-versus-host disease, which a CTA recipient can contract from immunologically active cells in specific tissue compartments inside a CTA and (3) the lack of good organ preservation technologies.; In each of these three areas a hypothesis was formulated that could potentially offer a solution for these impediments:; Hypothesis 1: By using small fusogenic vesicles, the membranes of endothelial cells in an allograft can be modified to carry proteins that may prevent rejection without the need for immunosuppression.; Hypothesis 2: The lymph nodes inside a CTA are responsible for GVHD following CTA. Removal of these lymph nodes prevents GVHD following CTA.; Hypothesis 3: Fusogenic vesicles loaded with Adenosine Triphosphate (ATP) can preserve composite tissue allografts for prolonged periods of time.; The dissertation is divided into seven chapters. Chapter 1 provides and introduction and the hypotheses for the dissertation. Chapter 2 gives a historical background on transplantation surgery and the problem of rejection, which the field still faces half a decade after the first kidney transplant. Chapter 3 then provides a clinical overview of the first four clinical hand transplantations and establishes the need for the work described in this dissertation. Chapter 4 then addresses Hypothesis 1 and offers a potential solution for the problem of immune rejection following CTA. Chapter 5 addresses Hypothesis 2 and identifies the lymph nodes as the compartment responsible for GVHD following CTA. Chapter 6 addresses the second part of Hypothesis 2 and offers a potential solution for the problem of GVHD following CTA. Chapter 7 addresses Hypothesis 3 and introduces a new methodology for tissue preservation of CTAs. Finally, Chapter 8 provides closing remarks and the conclusion for this dissertation. (Abstract shortened by UMI.)...