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B H Collins

Publications and source records attributed to B H Collins.

27 records · Page 2Linked to original sources
PubMed1995

Variation in the level of xenoantigen expression in porcine organs.

Hyperacute rejection of vascularized porcine to primate xenografts is initiated by the binding of xenoreactive natural antibodies to donor endothelium. We tested the hypothesis that the level of xenoantigen expression varies in the population of potential porcine donors and may determine the amount of binding of xenoreactive natural antibodies to a porcine organ perfused by xenogeneic blood. Two hundred ninety pigs were studied using an inhibition ELISA that quantitated the xenoantigen level on porcine platelets. Based on this assay, the levels of xenoantigen expression in the population adhered to a normal distribution. Kidneys from pigs found to express high antigen levels and kidneys from pigs found to express low antigen levels were perfused with baboon blood using an extracorporeal circuit. In multiple experiments, a significant difference was observed in the amount of xenoreactive natural antibody adsorbed by high antigen versus low antigen organs. Normalizing for the weight of the perfused organs and for levels of natural antibody in individual baboons, high antigen organs adsorbed 3.6 +/- 1.3 U of xenoreactive natural antibody/g and low antigen organs adsorbed -0.8 +/- 1.0 U of xenoreactive natural antibody/g (P < 0.002). Immunopathology of tissues from the perfused organs demonstrated more deposition of IgM and C4 in high than in low xenoantigen organs. The quantitative relationship between binding of xenoreactive natural antibodies to platelets and to whole organs suggests that platelets are a valid representation of endothelial cell antigen expression in vivo. Despite the probable importance of Gal alpha(1-3)Gal as an epitope recognized by xenoreactive natural antibodies, differences in the binding to platelets or to organs of the GS-I-B4 lectin that recognizes that sugar had no correlation with the differences in binding of IgM to these tissues. Variation in expression of xenoantigen may be exploited to selectively breed donors for xenotransplantation that are less susceptible to attack by xenoreactive natural antibodies.

Animals↗
PubMed1995

Cardiac xenografts between primate species provide evidence for the importance of the alpha-galactosyl determinant in hyperacute rejection.

Transplants performed between phylogenetically disparate species are subject to hyperacute rejection initiated by binding of xenoreactive natural Abs to endothelium in the donor organ. Binding of these Abs activates complement, leading to tissue injury and destruction of the graft. Human xenoreactive natural Abs recognize Gal alpha 1-3Gal beta 1-4GlcNAc (galactose alpha 1-3galactose beta 1-4-N-acetylglucosame); however, the relative importance of this Ag in graft rejection has not been proved. The present study was conducted to test the potential importance of alpha-galactosyl (alpha-Gal) determinants in the pathogenesis of hyperacute rejection. To this end, hearts (n = 3) from New World monkeys (Saimiri scureus, squirrel monkey), which can synthesize Gal alpha 1-3Gal, were transplanted heterotopically into Old World monkeys (Papio species, baboon), which do not synthesize Gal alpha 1-3Gal determinants and which have circulating anti-alpha Gal Abs. The xenografts were rejected in 51 to 56 min (mean +/- SD = 53.3 +/- 2.5), results similar to those observed in porcine grafts transplanted into baboons. Histologic analysis of the hearts revealed thrombosis and intraparenchymal hemorrhage and immune deposits consisting of IgM, Clq, C3, C4, C5b, and the membrane attack complex, but not properdin or factor B of the recipient deposited on graft endothelium. Sera obtained from baboons after perfusion of squirrel monkey kidneys revealed depletion of alpha-Gal-specific Abs and anti-pig endothelial cell Abs. These findings provide strong evidence that the Abs that accumulate in New World monkey organs during perfusion with baboon blood are the same Abs that would accumulate in a porcine organ transplanted into a primate and suggest that hyperacute rejection is not necessarily a reflection of phylogenetic distance but that the expression of terminal alpha-Gal residues provides an adequate target to initiate that process.

Animals↗
PubMed1995

Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation.

Immunoglobulins regulate the complement system by activating complement on foreign surfaces and diverting reactive complement proteins away from autologous cell surfaces. Based on this model, we explored the ability of Ig to balance complement activation versus control in a pig-to-primate cardiac xenotransplantation model in which the binding of xenoreactive antibodies of the recipient to graft blood vessels and the activation of complement cause hyperacute rejection. Human IgG added to human serum caused a dose-dependent decrease in deposition of iC3b, cytotoxicity, and heparan sulfate release when the serum was incubated with porcine endothelial cells. This decrease was not caused by alteration in antibody binding or consumption of complement but presumably reflected decreased formation of C3 convertase on the endothelial cells. Infusion of purified human IgG into nonhuman primates prevented hyperacute rejection of porcine hearts transplanted into the primates. As expected, the transplants contained deposits of recipient Ig and C1q but not other complement components. The inhibition of complement on endothelial cell surfaces and in the xenotransplantation model supports the idea that IgG regulates the classical complement pathway and supports therapeutic use of that agent in humoral-mediated disease.

Animals↗
PubMed1994

Mechanisms of injury in porcine livers perfused with blood of patients with fulminant hepatic failure.

Hyperacute rejection of renal and cardiac xenografts is initiated by the reaction of recipient natural antibodies and complement with endothelial cell antigens of the donor organ. The liver is thought to be less susceptible to this form of rejection; however, the mechanisms underlying its decreased susceptibility are not known. We investigated the organ injury occurring in porcine livers perfused with blood from 4 human subjects with fulminant hepatic failure. Nine porcine livers were perfused via an extracorporeal circuit in order to provide temporary metabolic support. Each porcine liver exhibited metabolic function, and the duration of xenoperfusion ranged from 2 to 5 hr. Histologic examination of the xenoperfused livers revealed focal hepatocellular necrosis, prominent infiltration of neutrophils, and, in 7 of 9 cases, periportal and centrilobular hemorrhage and thrombosis. Immunopathology demonstrated minimal or no human IgM and IgG along the small vessels and sinusoidal surfaces. Trace deposits of human IgM were observed along the luminal surfaces of large blood vessels in most cases. Trace deposits of C3 were noted in 2 of 9 livers; however, C4, iC3b, C5b, properdin, and the membrane attack complex were not detected. Human anti-porcine natural antibody titers decreased less than expected during the perfusions. Serum CH50, C3, and C4 levels were low before each procedure and decreased slightly with perfusion. One patient perfused 2 porcine livers and a human liver. The human liver had focal hepatocellular necrosis, trace deposits of IgM, no deposits of complement, and an infiltrate consisting of neutrophils; however, the neutrophil influx was less than that observed in the xenoperfused livers. To further evaluate the effects of alloperfusion, venovenous bypass was established in 2 pigs and the extracorporeal circuit was utilized to perfuse 2 porcine livers. The alloperfused porcine livers had focal hepatocellular necrosis and a minimal infiltrate of neutrophils. There were no deposits of porcine IgM, IgG, or complement components. In conclusion, although the porcine livers perfused by human blood sustained structural damage, the time course, the absence of immune deposits, and the findings of similar, albeit less severe, lesions in the alloperfused livers suggest that the pathogenesis of tissue injury in the xenoperfused livers differs from that of hyperacute rejection and may be related to the action of recipient neutrophils.

Adult↗
PubMed1994

The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts.

The use of xenografts (Xgs) from distantly related species to relieve the increasing shortage of organs for clinical transplantation is prevented by the occurrence of hyperacute rejection (HAR). This process, in which C activation plays a central role, cannot be inhibited with currently available immunosuppressants. In two clinically relevant xenotransplantation models, this study evaluated the effect of C inhibition using recombinant soluble complement receptor type 1 (sCR1) on HAR. In an ex vivo model in which porcine cardiac Xgs were perfused with human blood, cardiac function ceased within 34 min when the perfusate blood was untreated (n = 3). When the perfusate blood was treated with sCR1 (300 micrograms/ml), cardiac Xg function was maintained for up to 4 hr (n = 3). Immunohistologic examination of these Xgs demonstrated deposition of C3b/iC3b and C3d in Xgs perfused with untreated human blood but only C3d deposition in those Xgs perfused with sCR1-treated human blood. These findings are consistent with the cofactor activity of sCR1 for factor I-mediated degradation of deposited C3b/iC3b to C3d. Treatment with sCR1 also prevented the histopathologic changes of HAR observed when untreated blood was used as the perfusate. In an in vivo pig-to-primate heterotopic cardiac xenotransplantation model, in which porcine Xgs transplanted into untreated cynomolgus monkey recipients underwent HAR in 1 hr or less (n = 3), a single intravenous bolus of sCR1 (15 mg/kg) administered to the recipient immediately before Xg reperfusion markedly inhibited total and alternative pathway serum C activity and prolonged Xg survival to between 48 and 90 hr (n = 5). These studies confirm the important role of C activation in HAR of porcine cardiac Xgs by primates and indicate that sCR1 may be a useful agent for xenotransplantation.

Animals↗