Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Abstract

The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.

Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses

“…However, this is not the case for whole-organ liver transplants, where differences between many of the proteins manufactured in the liver (approximately 2,000) may prohibit adequate function. In addition, xenotransplantation of lungs will require more research into their physiology (225). It has become clear that coagulation dysfunction between recipient and donor, as well as inflammation, contributes significantly to different survival times and to the loss of the xenotransplant (262).…”

Lung Transplantation: Current Status and Challenges

“…Xenotransplantation from genetically modified pigs offers the most likely near-term prospect for alleviating the lung donor shortage, but lung xenografting poses formidable problems (123)(124)(125). Whether triggered primarily by cellular adhesive interactions or coagulation pathway incompatibilities, to fully prevent acute lung injury in this context, substantial additional work appears necessary.…”

ABO-incompatible lung transplantation

“…Abundant evidence indicates that the lung is particularly susceptible to injury by humoral mechanisms [6]. In addition to antibody and complement, cytokines, eicosanoids and coagulation cascade byproducts are humoral factors that have each been implicated in the pathogenesis of acute lung injury.…”

“…Multiple cytokines and other inflammatory mediators elaborated by these cells promote endothelial activation and coagulation cascade activation. Blood monocytes and platelets traversing the lung then adhere to and interact with activated lung endothelium [6]. Reciprocal activating events in these cell populations trigger elaboration of tissue-factor-expressing microparticles, which then trigger local (and systemic) coagulation pathway activation, inflammation and thrombosis.…”

“…The lung's response to immune injury mediated by antibody reactive with graft antigens is well established. Preformed and elicited antibodies are associated with acute lung injury in allograft [5] and xenograft models [6]. Antibody is also found in association with chronic rejection in animal models [7] and in man, where the antibody may be directed at HLA molecules [8,9] non-HLA epithelial or endothelial antigens [10,11].…”