A human-specific mutation limits nonhuman primate efficacy in preclinical xenotransplantation studies.

BACKGROUND: Patients diagnosed with fulminant hepatic failure face high mortality rates. A potential therapeutic approach for these patients is the use of extracorporeal porcine liver perfusion, to serve as a form of "liver dialysis." Previously, our laboratory has shown that, during a 72-hour extracorporeal perfusion with human blood, porcine Kupffer cells bind to and phagocytose human erythrocytes causing the hematocrit to fall to 2.5% of the original value. Subsequently, erythrocyte binding has been shown to involve N-acetylneuraminic acid (Neu5Ac) on the surface of human erythrocytes and sialoadhesin on the surface of the porcine Kupffer cells. METHODS: Given that no primate other than the human is known to express the majority of its sialic acid as Neu5Ac, we evaluated whether nonhuman primates would provide adequate evaluation of the loss of erythrocytes that might be expected in a clinical trial of extracorporeal porcine liver perfusion. RESULTS: We found that while porcine macrophages readily bound human erythrocytes, binding of nonhuman primate erythrocytes was significantly reduced (P<0.001). CONCLUSIONS: This study suggests that nonhuman primates may fail to serve as an adequate model for studying extracorporeal porcine liver perfusion because of the fact that porcine macrophages do not bind nonhuman primate erythrocytes.

Blocking porcine sialoadhesin improves extracorporeal porcine liver xenoperfusion with human blood.

BACKGROUND: Patients in fulminant hepatic failure currently do not have a temporary means of support while awaiting liver transplantation. A potential therapeutic approach for such patients is the use of extracorporeal perfusion with porcine livers as a form of "liver dialysis". During a 72-h extracorporeal perfusion of porcine livers with human blood, porcine Kupffer cells bind to and phagocytose human red blood cells (hRBC) causing the hematocrit to decrease to 2.5% of the original value. Our laboratory has identified porcine sialoadhesin expressed on Kupffer cells as the lectin responsible for binding N-acetylneuraminic acid on the surface of the hRBC. We evaluated whether blocking porcine sialoadhesin prevents the recognition and subsequent destruction of hRBCs seen during extracorporeal porcine liver xenoperfusion. METHODS: Ex vivo studies were performed using wild type pig livers perfused with isolated hRBCs for 72-h in the presence of an anti-porcine sialoadhesin antibody or isotype control. RESULTS: The addition of an anti-porcine sialoadhesin antibody to an extracorporeal porcine liver xenoperfusion model reduces the loss of hRBC over a 72-h period. Sustained liver function was demonstrated throughout the perfusion. CONCLUSIONS: This study illustrates the role of sialoadhesin in mediating the destruction of hRBCs in an extracorporeal porcine liver xenoperfusion model.

Immunobiology of liver xenotransplantation.

Pigs are currently the preferred species for future organ xenotransplantation. With advances in the development of genetically modified pigs, clinical xenotransplantation is becoming closer to reality. In preclinical studies (pig-to-nonhuman primate), the xenotransplantation of livers from pigs transgenic for human CD55 or from α1,3-galactosyltransferase gene-knockout pigs+/- transgenic for human CD46, is associated with survival of approximately 7-9 days. Although hepatic function, including coagulation, has proved to be satisfactory, the immediate development of thrombocytopenia is very limiting for pig liver xenotransplantation even as a 'bridge' to allotransplantation. Current studies are directed to understand the immunobiology of platelet activation, aggregation and phagocytosis, in particular the interaction between platelets and liver sinusoidal endothelial cells, hepatocytes and Kupffer cells, toward identifying interventions that may enable clinical application.

Efficacy of a novel air filtration pillow for avoidance of perennial allergens in symptomatic adults.

BACKGROUND: Nighttime allergen exposures are a primary contributor to the development of allergic and asthmatic morbidities. Disease management guidelines recommend the use of environmental control measures to reduce these exposures, but clinically relevant reductions are difficult to achieve because most measures control only 1 allergen source among many in the bedroom environment. OBJECTIVE: To determine whether a novel localized approach to nighttime allergen avoidance provides effective exposure reductions and clinical benefits. METHODS: Thirty-five adults with perennial allergic rhinoconjunctivitis (dog, cat, or dust mite sensitivity) were randomized to receive PureZone, a combination therapy involving localized air filtration and pillow encasement, or placebo in a crossover trial with two 2-week treatment periods separated by a 1-week washout. Nasal and ocular allergy symptoms, quality of life, and breathing zone particulate exposure were assessed. Bedroom allergen dust samples were collected in the sleeping environment. RESULTS: Reductions (>99.99%) in allergen-sized particulate (> or = 0.3 microm) in the breathing zone led to significant improvements in nocturnal nasal and ocular allergy symptoms (P < .001) and quality of life (P = .02) for the active vs placebo device. Significant nocturnal symptom reductions vs placebo occurred the second night of use and were maintained for the duration of treatment; these reductions improved sleep problems in particular (P = .02). Allergens were detected in 100% of bedrooms, of which 44% had levels that exceeded sensitizing thresholds. CONCLUSIONS: The combination therapy of pillow encasement and localized air filtration provided effective nighttime allergen exposure reductions and clinical benefits without the use of adjunctive therapy.