Overview

The impetus to develop the clinical application of xenografts is provided by the shortage of available human donor organs. For the example of end-stage lung disease, despite increasingly flexible donor acceptance criteria, about 20% of lung transplant candidates die while waiting [1] owing to lack of timely availability of suitable donor organs. Meanwhile arbitrary age restrictions are commonly used to exclude from consideration many other patients with end-stage lung and heart disease, primarily to minimize the imbalance between the waiting list and the supply of suitable donors. Xenotransplantation – in this instance of animal organs to humans – represents one potential solution to this problem. Ethical, logistic and infectious disease considerations have focused preclinical xenotransplant efforts on development of the pig as a potential donor species [2, 3].

The primary immunological barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR) (Figure 28.1); this phenomenon of immediate (within minutes or hours) capillary leak and parenchymal necrosis defines a ‘discordant’ xenograft [4]. Pig-to-human grafts are known to be discordant on the basis of several clinical attempts [5–8] and multiple other experiences with ex vivo perfusion of lungs, kidneys, livers, and hearts [5, 6, 9–15]. Additional possible barriers, including risk of introducing infection (‘xenozoonosis’) or fundamental biochemical incompatibilities, seem likely to prove manageable once the immune barriers are breached [16].

Scientific background: the role of antibody and complement in hyperacute rejection

The principal cause of HAR is activation of the ‘classical pathway’ of complement activation, which occurs subsequent to interaction of innate ‘natural’ antibody circulating in the blood of the recipient with target antigens in the graft [17].