Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-α(1,3)-galactose epitope (GalTKO) and to express human CD46, a complement regulatory protein, has not previously been described. Physiologic, hematologic and biochemical parameters during perfusion with heparinized fresh human blood were measured for 33 GalTKO.hCD46, GalTKO (n=16), and wild type pig lungs (n=16), and 12 pig lungs perfused with autologous pig blood. Median GalTKO.hCD46 lung survival was 171 minutes compared to 120 for GalTKO (p=0.27) and 10 for wild type lungs (p<0.001). Complement activation, platelet activation, and histamine elaboration were significantly reduced during the first 2h of perfusion in GalTKO.hCD46 lungs compared to GalTKO (ΔC3a at 120′ 812±230 vs. 1412±1047, p=0.02; ΔCD62P at 120′ 9.8±7.2 vs. 25.4±18.2, p<0.01; Δhistamine at 60′ 97±62 vs. 189±194, p=0.03). We conclude that, in addition to significant down-modulation of complement activation, hCD46 expression in GalTKO lungs diminished platelet and coagulation cascade activation, neutrophil sequestration and histamine release. Because GalTKO.hCD46 lung failure kinetics correlated directly with platelet and neutrophil sequestration, coagulation cascade activation, and a rise in histamine levels within the first hour of perfusion, further progress will likely depend upon improved control of these pathways, by rationally targeted additional modifications to pigs and pharmacologic interventions.

Organ transplantation is the preferred method of treatment for many forms of end-stage organ failure. However, immunosuppressive drugs that are used to avoid rejection can result in numerous undesirable effects (infection, malignancy, hypertension, diabetes, and accelerated arteriosclerosis). Moreover, they are not effective at preventing chronic rejection resulting in late graft loss. This review summarizes the fundamental concepts underlying the rejection of solid-organ allografts with the aim of highlighting potential new targets for therapeutics. Future improvement will depend on new therapeutic moieties, including biologics, to target various pathways of both the innate and adaptive arms of immunity. Results from some of the most recent clinical trials in transplantation and emerging new therapies are also discussed.

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