Biomedical subjects
Publications and source records attributed to D K Cooper.
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The baboon, like the human, expresses A and/or B blood group antigens on its tissues. Anti-A and anti-B antibodies are directed against these antigens, the epitopes of which are carbohydrate structures. Portions of these carbohydrates have been synthesized (trisaccharides A and B, respectively). When infused intravenously, the synthetic trisaccharides form a complex with the specific antibodies and neutralize their activity preventing them from binding to the antigen targets on a transplanted organ. In nonimmunosuppressed, hyperimmunized baboons, the continuous intravenous infusion of the specific trisaccharide alone (for 6 days) inhibited rejection of ABO-incompatible cardiac allografts, extending survival from a mean of 19 min (n = 3) to 8 days (n = 2), at which time the grafts failed from cellular (not vascular) rejection. The combination of long-term pharmacologic immunosuppression plus trisaccharide infusion (for periods of 8 to 19 days) extended survival to a mean of > 28 days (n = 4) with one heart functioning > 52 days. Accommodation clearly occurred in three of the four cases. This form of therapy may permit cadaveric organ allotransplantation across the ABO blood-group barrier in the human.
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Atrioventricular (AV) nodal reentrant tachycardia and atrial flutter are considered 2 distinct supraventricular tachycardias. Recent clinical and experimental data suggest that both these tachycardias include an area in the lower right atrial septum in their reentrant pathways. This study was designed to test the hypothesis that there is an association between the mechanisms of AV nodal reentrant tachycardia and atrial flutter because of a shared pathway of reentry. Consecutive patients referred for evaluation and management of supraventricular tachycardia, thought to be due to AV nodal reentry, underwent electrophysiologic testing protocols designed to induce both AV nodal reentrant tachycardia and atrial flutter, if present. Fifteen of 29 patients (52%) had both AV nodal reentrant tachycardia and atrial flutter induced during electrophysiologic testing. Seven of these 15 patients (47%) underwent transcatheter radiofrequency current application (mean power 34 +/- 4 W) against the tricuspid annulus above the coronary sinus. In each patient, neither AV nodal reentrant tachycardia nor atrial flutter could be induced after the procedure. Repeat study after successful ablation (mean 6 days) showed no inducible supraventricular arrhythmia of either type at baseline study or during isoproterenol infusion. Atrial flutter occurs frequently (15 of 29 patients; 52%) in patients with AV nodal reentrant tachycardia, because of a shared pathway in their reentry circuits. Because of this shared pathway, both arrhythmias can be ablated at the same site. These observations promote new insights into the mechanism and therapeutics of supraventricular tachycardias.
Preformed human anti-pig antibodies isolated from perfused pig hearts were used to analyze the binding of various immunoglobulin classes to cultured pig kidney cells. All anti-pig immunoglobulins (i.e., IgG, IgA, and IgM) were localized on the cell surface by the use of an indirect immunofluorescence technique. Anti-pig immunoglobulins also competed for the pig cell surface epitopes with Griffonia simplicifolia lectin (GS-I-B4), which is specific for alpha-galactosyl residues. This study provides further evidence that preformed human antibodies recognizing alpha-galactosyl-containing epitopes (anti-gal antibodies) could be an important factor in hyperacute rejection of pig organs.
A methyl methacrylate plate was fashioned to maintain the sternum in the open position in a patient with impaired donor heart function after transplantation. Bilateral mammary flaps enabled soft tissue and skin closure. The chest wall fixation obtained allowed extubation and spontaneous breathing. The plate was subsequently removed. The patient remains well almost 3 years later.
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Human anti-pig antibodies were obtained by perfusing pig hearts (n = 4) and kidneys (n = 8) with human AB or O plasma followed by elution with 3 M NaSCN. The antibodies were screened against a panel of 132 synthetic carbohydrates conjugated to bovine serum albumin using an enzyme-linked immunoassay. An anti-immunoglobulin antibody was also used to detect immunoglobulin deposits on pig tissues. Four carbohydrate molecules with a terminal alpha-galactose residue bound all but one of the human anti-pig kidney antibodies and most of the anti-pig heart antibodies. These were: (i) alpha Gal(1-->3)beta Gal(1-->4)beta GlcNac (linear B type 2); (ii) alpha Gal(1-->3)beta Gal(1-->4)beta Glc (linear B type 6); (iii) alpha Gal(1-->3)beta Gal(B disaccharide); and (iv) alpha Gal(alpha-D-galactose). Immunoglobulin deposition was documented post-plasma perfusion in all pig hearts and particularly strongly in all pig kidneys. These results suggest that human anti-pig antibodies are mainly directed against alpha-galactosyl structures. Extracorporeal immunoadsorption of human plasma through columns of the specific synthetic carbohydrate(s) might lead to depletion of anti-pig antibodies and allow discordant xenografting in man. Alternatively, the infusion of the specific carbohydrate(s) for a period of several days might result in neutralization of the anti-pig antibodies and allow accommodation to take place.
Heterotopic allografting of ABO-incompatible donor hearts in recipient baboons "hyperimmunized" against the incompatible A or B antigen (n = 3) was followed by hyperacute antibody-mediated vascular rejection within a mean of 19 min. The A and B epitopes against which these antibodies are directed are carbohydrates that can be synthesized. The continuous i.v. infusion of the specific synthetic A or B trisaccharide, beginning immediately pre-transplant and continued posttransplant for several days, prolonged allograft survival to a mean of 8 days (n = 2) and prevented antibody-mediated rejection, graft failure resulting from acute cellular rejection. The addition of triple pharmacologic immunosuppressive therapy (n = 4) resulted in prolongation of graft survival to a mean of > 28 days, with one heart still beating at 52 days; all grafts showed features of cellular rejection. "Accommodation" would appear to have developed in several baboons as graft function continued for periods of up to 39 days after discontinuation of carbohydrate therapy. Specific i.v. carbohydrate therapy should allow organ allografting to be performed across the ABO blood group barrier in humans. Furthermore, if the carbohydrate epitopes on the organs of discordant animals (e.g., the pig) against which human xenoreactive antibodies are directed can be confirmed, then this form of therapy might allow successful discordant organ xenotransplantation in man.
Pig tissues were screened by immunofluorescence with lectins, mAb, and human natural antibodies for the presence of carbohydrate antigens, which may be potential targets for hyperacute vascular rejection in pig to man xenotransplantation. The unfucosylated monomorph linear B-antigen was found at the surface of all porcine vascular endothelial cells. This pig linear-B antigen reacts strongly with the anti-alpha Gal isolectin B4 from Griffonia simplicifolia 1 and with human natural anti-alpha Gal antibodies specifically purified by affinity chromatography on synthetic oligosaccharides containing the terminal nonreducing alpha Gal1-->3 beta Gal-R disaccharide. This antigenic activity is destroyed by treatment of pig tissues with alpha-galactosidase. The localization of this linear-B epitope on vascular endothelium and its reactivity with natural human anti-alpha Gal antibodies suggest that it may play a major role in the hyperacute vascular rejection of pig to man organ xenografts. The lectin from Maackia amurensis reacting with alpha NeuAc2-->3 beta Gal1-->4GlcNAc/Glc was also positive on pig vascular endothelium, but we do not know yet whether there are human natural antibodies reacting with the carbohydrate recognized by this lectin. Epithelial cells of pig renal proximal convoluted tubules, respiratory epithelium, pancreatic ducts, and epidermis express the linear-B antigen, but they are less likely to trigger a hyperacute vascular rejection because they are not directly exposed to the blood. The genetically defined pig A+/A- system controls the expression of A and H antigens in pig epithelial cells from renal distal and collecting tubules, biliary ducts, pancreatic ducts, large bronchi, and digestive mucosa. The pig A antigen may trigger an immune response in human O or B recipients if they are transplanted with organs from A+ pigs, but the pig A antigen is probably not involved in the hyperacute vascular rejection of a xenograft because it is not expressed on vascular endothelium.
We describe a technique for "orthotopic" heart transplantation in a patient with situs inversus. The left atrial, aortic, and pulmonary artery anastomoses were performed directly, in the usual manner. The recipient's right atrium was converted into a tunnel, and the donor's right atrium was left intact. Anastomoses were therefore required between the 2 inferior venae cavae (by direct end-to-end anastomosis) and the 2 superior venae cavae (necessitating the insertion of a Dacron-graft). We suggest that even simpler techniques, perhaps not requiring the use of an artificial vascular prosthesis, are possible.