Mechanisms of pig-to-primate xenograft rejection
Subtitle: preclinical and basic studies.
Published: 2004
Language: eng
Number of pages: 200
Description: Xenotransplantation offers a solution to the shortage of human organs for transplantation. The current barrier to survival of pig-to-primate xenografts is acute vascular rejection (AVR). AVR is characterized by endothelial injury and intravascular thrombosis, and is associated with deposition of antibodies and fibrin. AVR pathophysiology is poorly understood, but is thought to involve xenoreactive antibodies and disordered thromboregulation.We therefore investigated whether induction of the immune coagulant fibrinogen-like protein 2 (fgl2) contributes to AVR. The porcine fgl2 (pfgl2) was cloned and observed to activate human prothrombin in vitro. AVR of pig-to-baboon kidney xenografts was associated with induction of pfgl2 in endothelial cells (EC). Activation of porcine EC by human TNFalpha, but not by xenoantibodies, resulted in induction of pfgl2 and prothrombinase activity. Using a mouse-to-rat cardiac xenotransplantation model, in which high-titre xenoreactive antibodies are absent, hearts from fgl2+/+ and fgl2 +/- mice developed AVR and thrombosis in association with endothelial induction of fgl2. In contrast, thrombosis was significantly ameliorated in hearts from fgl2-deficient (fgl2-/-) mice. These observations suggested that antibody-independent endothelial induction of fgl2 contributes to AVR-associated thrombosis.These studies offer new insights into AVR pathophysiology by illustrating the relevance of xenoantibodies as well as the role of a novel antibody-independent pathway of immune coagulation, fgl2. Further studies incorporating manipulation of these factors may yield novel strategies by which to overcome AVR and extend porcine xenograft survival towards clinical utility.We first examined whether depleting antibodies would prevent AVR of life-supporting pig-to-baboon kidney xenografts. Depletion of recipient antibodies against the alpha-gal xenoantigen, combined with immunosuppression to prevent antibody responses, ameliorated AVR. Effective protocols consisted of GAS (alpha-gal analogue) with cyclophosphamide, cyclosporine, steroids and rapamycin, or GAS with rabbit antithymocyte serum, cyclosporine, steroids and splenectomy, with or without rapamycin. Recipient survival was not improved because baboons that did not succumb to rejection were lost to complications of immunosuppression. These studies demonstrated that preformed and elicited xenoantibodies contribute to the pathogenesis of AVR. Failure of these strategies to fully prevent AVR suggested that more effective means of suppressing xenoantibodies are required or that antibody-independent mechanisms such as disordered thromboregulation contribute to xenograft rejection.
Notes: Adviser:  Gary Levy.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 5057.