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David K C Cooper

Publications and source records attributed to David K C Cooper.

At least 55 records · Page 3Linked to original sources
PubMed2004

alpha1,3-Galactosyltransferase gene-knockout miniature swine produce natural cytotoxic anti-Gal antibodies.

BACKGROUND: The expression of galactose alpha 1,3 galactose (Gal) in pigs has proved a barrier to xenotransplantation. Miniature swine lacking Gal (Gal pigs) have been produced by nuclear transfer/embryo transfer. METHODS: The tissues of five Gal pigs of SLA dd haplotype (SLA) were tested for the presence of Gal epitopes by staining with the Griffonia simplicifolia IB4 lectin. Their sera were tested by flow cytometry for binding of IgM and IgG to peripheral blood mononuclear cells (PBMC) from wild-type (Gal) SLA-matched pigs; serum cytotoxicity was also assessed. The cellular responses of PBMC from Gal swine toward Gal SLA-matched PBMC were tested by mixed leukocyte reaction and cell-mediated lympholysis assays. RESULTS: None of the tissues tested showed Gal expression. Sera from all five Gal pigs manifested IgM binding to Gal pig PBMC, and sera from three showed IgG binding. In all five cases, cytotoxicity to Gal cells could be demonstrated, which was lost after treatment of the sera with dithiothreitol, indicating IgM antibody-mediated cytotoxicity. PBMC from Gal swine had no proliferative or cytolytic T-cell response toward Gal SLA-matched PBMC. CONCLUSIONS: Gal pigs do not express Gal epitopes and develop anti-Gal antibodies that are cytotoxic to Gal pig cells. The absence of an in vitro cellular immune response between Gal and Gal pigs is related to their identical SLA haplotype and indicates the absence of immunogenicity of Gal in T-cell responses. The model of Gal organ transplantation into a Gal SLA-matched recipient would be a valuable large animal model in the study of accommodation or B-cell tolerance.

Animals↗
PubMed2004

Acute vascular rejection of xenografts: roles of natural and elicited xenoreactive antibodies in activation of vascular endothelial cells and induction of procoagulant activity.

BACKGROUND: Hyperacute rejection of vascularized discordant xenografts can now be effectively managed. However, acute vascular rejection (AVR) then ensues, resulting in graft destruction, coagulopathy, or both within weeks. The aim of this study was to determine associations between humoral responses to the xenograft and the induction of AVR, coagulopathy, or both. METHODS: In vitro, heat-inactivated, naive or sensitized baboon sera containing xenoreactive natural or elicited antibodies were used to activate porcine aortic endothelial cells (PAEC) in vitro. Tissue factor expression on PAEC was determined as an index of heightened procoagulant activity. In vivo, porcine renal xenografts were transplanted into immunosuppressed baboons, and at the time of rejection or the development of a consumptive coagulopathy, biopsy specimens were obtained for studies of xenoreactive antibody binding and tissue factor expression. RESULTS: In vitro, incubation of PAEC with naive baboon sera containing natural anti-Galalpha1,3Gal (Gal) antibodies resulted in minimal tissue factor induction; the addition of complement boosted procoagulant responses. Elicited xenoreactive antibodies, and to non-Gal epitopes alone, induced high amounts of procoagulant activity on PAEC; the addition of complement resulted in overt cytotoxicity. In vivo, AVR was associated with xenoreactive antibody deposition in the graft. When vascular endothelial binding of xenoreactive antibody was combined with the expression of tissue factor, consumptive coagulopathy developed irrespective of histopathologic features of AVR. CONCLUSIONS: Our in vitro results indicate that elicited antibodies, potentially to non-Gal epitopes, induce endothelial cell activation and tissue factor expression; in vivo, a consumptive coagulopathy occurred when there was xenoreactive antibody deposition and increase of tissue factor.

Acute Disease↗
PubMed2004

Activation of porcine cytomegalovirus, but not porcine lymphotropic herpesvirus, in pig-to-baboon xenotransplantation.

Tissue-invasive disease due to porcine cytomegalovirus (PCMV) has been demonstrated after pig-to-baboon solid-organ xenotransplantation. Porcine lymphotropic herpesvirus (PLHV)-1 is associated with B cell proliferation and posttransplant lymphoproliferative disorder after allogeneic bone marrow transplantation in swine but has not been observed in pig-to-primate xenotransplantation. Activation of PCMV and PLHV-1 was investigated in 22 pig-to-baboon xenotransplants by use of quantitative polymerase chain reaction. PCMV was found in all xenografts; increased viral replication occurred in 68% of xenografts during immunosuppression. PLHV-1 was found in 12 xenografts (55%); no increases in viral replication occurred during immunosuppression. Control immunosuppressed swine coinfected with PCMV and PLHV-1 had activation of PCMV but not PLHV-1. PCMV, but not PLHV-1, is activated in solid-organ xenotransplantation.

Animals↗
PubMed2004

Non-specific removal of antibodies in patients with idiopathic dilated cardiomyopathy: implications for xenotransplantation.

We assessed the efficiency of non-specific extracorporeal immunoadsorption (EIA), using polyclonal anti-human immunoglobulin antibodies, in depleting the serum of anti-galactosealpha1,3galactose (Gal) antibody and in decreasing serum cytotoxicity in 5 patients with idiopathic dilated cardiomyopathy. The mean concentrations of anti-Gal immunoglobulin (Ig)M and IgG before EIA were 74 microg/ml and 159 microg/ml, respectively. After EIA, these concentrations decreased by 86% and 88%, respectively. Both anti-Gal IgM and IgG returned to pre-EIA concentrations within 1 month, without rebound to greater than baseline concentrations. After EIA, mean serum cytotoxicity also decreased from 90% to 17%, with recovery by 1 month. Extracorporeal immunoadsorption proved safe in patients with heart failure and was effective in depleting anti-Gal antibody and in decreasing serum cytotoxicity to pig cells.

Adult↗
PubMed2004

Relative effects of GAL+ and GALlow/- porcine hematopoietic cells on primate platelet aggregation and endothelial cell activation: implications for the induction of mixed hematopoietic chimerism in the pig-to-primate model.

BACKGROUND: The induction of porcine hematopoietic cell chimerism in preconditioned baboons has been hampered by the development of thrombotic microangiopathy. As pigs that lack expression of Gal alpha 1,3 Gal (Gal) may become available in the near future, we have explored the effects of porcine hematopoietic cells that express low or no Gal (Gal(low/-)) on baboon platelet aggregation and on human umbilical vein endothelial cell (HUVEC) activation. METHODS: Porcine mobilized peripheral blood progenitor cells (PBPC; Gal(+)) and bone marrow mononuclear cells (BM; Gal(+) or Gal(low/-)) were investigated for their potential to (i) induce aggregation of baboon platelets, and (ii) to activate endothelial cells as measured by increased expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin on HUVEC. alpha-Galactosidase-treated PBPC were also investigated for their effect on platelet aggregation. RESULTS: Gal(+) PBPC and Gal(+) BM cells (10(7)) induced aggregation of baboon platelets by 42 and 31%, respectively, whereas Gal(low/-) BM cells did not induce any platelet aggregation. alpha-Galactosidase-treated PBPC induced less platelet aggregation than untreated PBPC. Gal(+) PBPC and Gal(+) BM cells (10(7)) increased expression of VCAM-1, ICAM-1 and E-selectin on HUVEC, whereas Gal(low/-) BM cells did not. CONCLUSIONS: In contrast to Gal(+) PBPC or BM, Gal(low/-) BM cells do not induce aggregation of baboon platelets or activate HUVEC. The induction of tolerance through mixed hematopoietic cell chimerism may be facilitated when alpha-galactosyltransferase-knockout pigs become available.

Animals↗
PubMed2004

Initial investigation of the potential of modified porcine erythrocytes for transfusion in primates.

There is a shortage of human blood for transfusion. The possibility of using alpha-galactosidase-treated pig red blood cells (pRBCs) for transfusion into humans has been investigated. pRBCs were treated in vitro with alpha-galactosidase. In vitro binding of antibodies (Abs) in baboon or human sera to untreated/treated pRBCs was assessed by flow cytometry and serum cytotoxicity. In vivo clearance rates of (1) autologous baboon red blood cells (RBCs), (2) unmodified pRBCs, and (3) alpha-galactosidase-treated pRBCs were measured after transfusion into baboons receiving either no treatment or depletion of complement +/- depletion of anti-Gal alpha 1-3Gal (Gal) Ab or of macrophage phagocytes. In vitro binding of baboon or human Abs to treated pRBCs was absent or minimal compared with untreated pRBCs, and serum cytotoxicity was completely inhibited. In vivo autologous baboon RBCs survived for >16 days and unmodified pRBCs for <15 min in an untreated baboon. Treated pRBCs survived for 2 h in an untreated baboon, for 24 h in a complement-depleted baboon, and for 72 h when the baboon was depleted of both complement and anti-Gal Ab, or of complement and macrophage phagocytes. All baboons, however, became sensitized to Gal antigens. Failure to prolong the in vivo survival of treated pRBCs could be due to inadequate removal of Gal epitopes because sensitization to Gal developed, or could imply other, as yet unidentified, causes for RBC destruction. To fully assess the potential of pRBC transfusion in humans, more complete alpha-galactosidase treatment of pRBCs will be required.

Animals↗
PubMed2004

Thrombotic microangiopathy and graft arteriopathy in pig hearts following transplantation into baboons.

BACKGROUND: Acute humoral xenograft rejection (AHXR) is an immunologic barrier in pig-to-baboon organ transplantation (Tx). We report microvascular thrombosis and myocardial necrosis in a series of cardiac xenografts. METHODS: Ten baboons underwent heterotopic heart Tx from pigs transgenic for human decay-accelerating factor. Recipients were treated with soluble Gal glycoconjugates and multiple immunosuppressive agents. Grafts were removed when palpable contractions stopped. Stained tissue sections from harvested grafts were analyzed by light and fluorescence microscopy. RESULTS: Xenograft survival ranged from 4 to 139 (mean 37, median 27) days. Some histology was typical for AHXR (n = 4; median survival 22 days). Hemorrhage and edema were only focal in the longer-surviving grafts (n = 4, median survival 54 days). All grafts had multiple platelet-rich fibrin thrombi occluding myocardial vessels. Ischemic damage was manifested by contraction band necrosis in four grafts, myocytolysis in eight, coagulative necrosis in nine, and patchy myocyte dropout in all grafts. A notable paucity of interstitial mononuclear cells was observed in all grafts. Marked intimal thickening resembling that of allograft vasculopathy was observed in one graft. Immunofluorescence showed immunoglobulin (Ig)G and/or IgM deposition in five grafts. Multivessel C4d deposition appeared in seven grafts. Significant C3 deposition was absent. CONCLUSIONS: Cardiac xenograft survival in the pig-to-baboon model can be significantly prolonged by vigorous immunosuppressive treatment of recipient animals. Additional efforts to block humoral activation of graft endothelial cells and/or to overcome species-specific molecular coagulation pathway incompatibilities may prevent the development of microvascular thrombosis and myocardial infarction. Cardiac xenograft vasculopathy (chronic rejection) can occur with prolonged graft survival.

Acute Disease↗
PubMed2004

Investigation of red blood cells from alpha1,3-galactosyltransferase-knockout pigs for human blood transfusion.

BACKGROUND: Pigs are a potential source of red blood cells (RBCs) for transfusion into humans, but the presence of galactose-alpha1,3-galactose (Gal) epitopes on their surface, against which humans have anti-Gal, has been perceived as a major barrier. alpha1,3-Galactosyltransferase gene-knockout pigs, which do not express Gal epitopes on RBCs (Gal-/-), have recently become available. STUDY DESIGN AND METHODS: In vitro, RBCs from Gal-/- pigs were exposed to sera from naïve humans or baboons or from baboons previously sensitized to pig antigens; immunoglobulin binding was measured by flow cytometry, and cytotoxicity, by a hemolytic assay. In vivo, relatively small numbers of Gal-/- RBCs were transfused into two nonsensitized untreated baboons. The survival of pig RBCs was detected by flow cytometry. RESULTS: In vitro, binding of immunoglobulin (Ig) M from naïve human or baboon sera was detected to Gal-/- RBCs but was significantly less than to Gal+/+ RBCs; IgG binding to Gal-/- RBCs was absent or minimal. Sera had minimal cytotoxicity to Gal-/- RBCs compared to Gal+/+ RBCs. Sensitized baboon sera demonstrated much higher IgG binding to Gal-/- RBCs and increased cytotoxicity, but again these were less than to Gal+/+ RBCs. In vivo, the transfusion of relatively small volumes of Gal-/- RBCs was followed by detection of the cells in the baboon's blood for only 5 minutes. CONCLUSION: Pig RBCs are rapidly phagocytosed from the primate circulation by a mechanism not involving anti-Gal.

Animals↗
PubMed2004

Suppression of natural and elicited antibodies in pig-to-baboon heart transplantation using a human anti-human CD154 mAb-based regimen.

Natural and elicited antipig antibodies (Abs) lead to acute humoral xenograft rejection (AHXR). Ten baboons underwent heterotopic heart transplantation (Tx) from human decay-accelerating factor (hDAF) pigs. Depletion of anti-Galalpha1, 3Gal (Gal) Abs was achieved by the infusion of a Gal glycoconjugate from day-1. Immunosuppression included induction of antithymocyte globulin, thymic irradiation, and cobra venom factor, and maintenance with a human antihuman CD154 mAb, mycophenolate mofetil, and methylprednisolone; heparin and prophylactic ganciclovir were also administered. Pig heart survival ranged from 4 to 139 (mean 37, median 27) days, with three functioning for >50 days. Graft failure (n = 8) was from classical AHXR [4], thrombotic microangiopathy [3], or intragraft thrombosis [1], with death (n = 2) from pneumonia [1], or possible drug toxicity (with features of thrombotic microangiopathy) [1]. Anti-Gal Abs (in microg/mL) were depleted by Gal glycoconjugate before graft implantation from means of 41.3 to 6.3 (IgM) and 12.4-4.6 (IgG), respectively, and at graft excision were 6.3 and 1.7 microg/mL, respectively. No elicited Abs developed, and no cellular infiltration was seen. The treatment regimen was effective in maintaining low anti-Gal Ab levels and in delaying or preventing AHXR. The combination of costimulatory blockade and heparin with Tx of a Gal-negative pig organ may prolong graft survival further.

Animals↗
PubMed2004

The surgical anatomy of experimental and clinical thoracic organ transplantation.

The experimental investigation of heart transplantation began almost 100 years ago, but it was not until the studies at Stanford Medical School in the late 1950s and early 1960s that clinical transplantation became a realistic possibility. Barnard performed the 1st human-to-human orthotopic heart transplantation in 1967 and followed this by introducing the technique of heterotopic heart transplantation in 1974. Reitz and colleagues at Stanford performed the 1st successful clinical transplantation of the heart and both lungs in 1981. Two years later, at the Toronto General Hospital, successful single-lung transplantation was performed, followed by bilateral lung transplantation in 1986. Aspects of the surgical techniques of these various experimental and clinical procedures are discussed.

Biomedical Research↗
PubMed2003

Clinical xenotransplantion--how close are we?

CONTEXT: Xenotransplantation with pig organs offers a medium-term solution to the shortage of organs available for clinical transplantation. The immunological barriers to xenotransplantation have been, and remain, formidable. In the early 1990s, the identification of Galalpha1,3Gal (Gal) as the main target for human xenoreactive (anti-pig) antibodies and the development of pigs transgenic for a human complement regulatory protein, decay-accelerating factor (hDAF), were major advances. The presence of hDAF on the vascular endothelium of pig organs provided some protection against complement-mediated hyperacute rejection. This protection, however, was short-lived, and, until recently, the longest median time for organ survival that had been achieved (with combinations of biological and pharmacological immunosuppressants) in a series of pig-to-primate organ transplants was under a month. STARTING POINT: Christopher McGregor and colleagues recently reported to the International Society of Heart and Lung Transplantation (J Heart Lung Transplant 2003; 22: S89) that, by combining the use of organs which express hDAF with the administration of a soluble Gal glycoconjugate and other immunosuppressive agents, the survival of pig hearts in baboons can be extended to a median of 76 days. McGregor's work suggests that immunological barriers to xenotransplantation are not insurmountable. WHERE NEXT? The recent generation of pigs that do not express Gal epitopes (alpha1,3-galactosyltransferase gene-knockout pigs) might remove the need both for the expression of hDAF and the administration of a soluble Gal glycoconjugate. The absence of a natural antibody response will allow investigation of the cellular immune response and of any molecular incompatibilities between pig and primate that may be detrimental to graft survival. Furthermore, the absence of a humoral response may open the way for the induction of immunological tolerance (or unresponsiveness in the absence of exogenous immunosuppression) to a transplanted pig organ.

Animals↗
PubMed2003

Can spleen transplantation induce tolerance? A review of the literature.

In some rodent strain combinations, allogeneic spleen transplantation induces tolerance spontaneously to itself and to other donor-specific organs. In other combinations, a state of tolerance has been achieved in the weakened immune system of the recipient. The data indicate that if a balance can be achieved between host-versus-graft and graft-versus-host responses, tolerance develops, possibly due to the development of suppressor/regulatory cells. There have been a number of unsuccessful studies in outbred large animals, but none in MHC-defined donor-recipient pairs, and none in which the protocol specifically aimed at inducing tolerance. Spleen transplantation has been performed in approximately 50 humans for a number of reasons, however no clear immunologic advantage has been reported. Graft-versus-host disease (GVHD) was documented in at least 3 patients, and was lethal in one case, despite excision of the donor spleen. The advantages of tolerance over chronic immunosuppressive therapy are so great that a potentially tolerogenic approach such as spleen transplantation would seem worthy of further investigation in a suitable large animal model. Such a study is ongoing at our center.

Animals↗
PubMed2003

Porcine cytomegalovirus and coagulopathy in pig-to-primate xenotransplantation.

BACKGROUND: A rapidly progressive disorder termed consumptive coagulopathy (CC) has been observed frequently in pig-to-baboon renal xenotransplantation. CC may be initiated by endothelial activation and induction of procoagulant factors after immunologic injury or infection, or by molecular incompatibilities between porcine coagulation proteins and primate clotting factors. The activation of porcine (P) cytomegalovirus (PCMV) and baboon (B) CMV infections has been documented in pig-to-primate xenotransplantation. The purpose of this study was to determine the contribution of PCMV and BCMV to CC. METHODS: Endothelial activation was assessed by means of measurement of porcine tissue factor (pTF) in a functional assay in primary porcine aortic endothelial cells (PAEC) in vitro. Renal xenografts and native kidneys were studied by immunohistochemistry in immunosuppressed swine and baboons. BCMV and PCMV DNA was measured by quantitative molecular assays using real-time polymerase chain reaction. RESULTS: In vitro, infection of PAEC with PCMV resulted in a significant increase of pTF expression. In vivo, pTF increase occurred without the activation of PCMV in two xenografts, and in four grafts no pTF was detected despite PCMV activation. All animals with graft pTF increase developed CC. BCMV activation in the baboon xenograft recipients did not correlate with CC or pTF increase. Control pigs and baboons had activation of PCMV and BCMV, respectively, but without coagulation abnormalities. CONCLUSIONS: PCMV induces endothelial cell activation in vitro with procoagulant expression. However, in vivo, CC and pTF induction has an uncertain relationship to increased replication of PCMV within a xenograft. Although the data do not exclude a contributory role of PCMV in CC, other mechanisms are also likely to contribute to coagulopathies observed in pig-to-primate xenotransplantation.

Animals↗
PubMed2003

Xenogeneic thymokidney and thymic tissue transplantation in a pig-to-baboon model: I. Evidence for pig-specific T-cell unresponsiveness.

BACKGROUND: The potential of xenotransplantation for clinical application will require overcoming barriers of humoral and cellular rejection, through strategies using immune suppression or tolerance induction. This laboratory has previously reported the induction of tolerance in the discordant xenogeneic model of pig-to-rodent thymic transplantation. We also have described a miniature swine model of fully mismatched allogeneic composite vascularized thymokidney transplantation that induced transplantation tolerance. We tested a combination of these approaches in a clinically relevant pig-to-primate model of xenotransplantation. METHODS: Composite thymokidney grafts were prepared 40 to 80 days before transplantation by the autologous implantation of thymic tissue under the renal capsule of human decay-accelerating factor transgenic swine. Baboons received xenotransplants of both human decay-accelerating factor composite thymokidneys and omental implants of thymic tissue. Recipients were treated with an immunosuppressive-conditioning regimen including thymectomy or thymic irradiation, extracorporeal immunoadsorption of anti-alphaGal antibodies and T-cell depletion. Recipients were followed for indicators of xenograft rejection, T-cell depletion and reconstitution, anti-alphaGal antibody levels, and mixed lymphocyte responses. Immunologic responses were studied in those animals that survived for more than 3 weeks. RESULTS: Thymokidney xenografts survived for up to 30 days, with evidence of viable thymic epithelium and Hassall's corpuscles under the renal capsule and in the omental implants, and with evidence of few host lymphocytes. Three animals demonstrated donor-specific unresponsiveness, while maintaining normal alloresponses, in mixed-lymphocyte-response assays performed after immunosuppression had been stopped. Rejected grafts demonstrated humoral damage without evidence of cellular infiltrates. After graftectomy, one animal maintained donor-specific cellular unresponsiveness and stable anti-alphaGal antibody levels for more than 2 months. CONCLUSIONS: We concluded that composite thymokidney and thymic-tissue xenotransplantation from swine to baboons can induce donor-specific cellular unresponsiveness and stable anti-alphaGal antibody levels, suggesting avoidance of sensitization after xenotransplantation. The presence of viable donor-swine thymic epithelium could have a role in the development of donor-specific T-cell tolerance. Further strategies to address humoral rejection could prolong graft survival and result in long-term tolerance to xenografts.

Animals↗
PubMed2003

ABO-incompatible organ and bone marrow transplantation: current status.

Despite the presence of preformed antibodies against AB oligosaccharide epitopes on the donor vascular endothelium, approximately one-third of ABO-incompatible organ allografts are not rejected by a humoral mechanism. With the growing immune-manipulation of the recipient, survival rates can be raised considerably, although they remain significantly inferior to those of ABO-compatible transplantation. Data from the Collaborative Transplant Study indicate a 1-year graft survival rate of approximately 50-60% following cadaveric ABO-incompatible kidney, liver or heart transplantation, compared with 70-80% for an ABO-compatible organ. The results for infants and young children, however, are very much better than those of adults, particularly for liver and heart transplantations, and the data suggest that B-cell tolerance can develop in the infant age group. We here review clinical and experimental experience with ABO-incompatible organ and bone marrow allotransplantation and address the mechanisms by which organs or cells survive in the presence of natural anti-carbohydrate antibodies.

ABO Blood-Group System↗
PubMed2003

Xenogeneic thymus transplantation in a pig-to-baboon model.

BACKGROUND: We have tested whether fetal porcine thymic tissue transplantation can lead to tolerance across a discordant (pig-to-baboon) xenogeneic barrier. METHODS: Six baboons underwent a conditioning regimen with thymectomy, splenectomy, and anti-monkey CD3 antibody conjugated to a diphtheria toxin binding site mutant (FN18-CRM9). Porcine fetal or neonatal thymic tissue was transplanted into three baboons. Three control baboons received either no transplanted pig tissue (n=1) or adult pig lymph node (n=2). Cellular responses and skin xenografts were used to test for tolerance. RESULTS: After T-cell depletion and thymic transplantation, recovery of thymus-dependent naïve-type CD4 cells (CD4/CD45RA ) and in vitro xenogeneic hyporesponsiveness were observed. No sensitization of alpha-galactosyl antibody responses was observed. The thymic grafts survived up to 48 days. Porcine skin xenografts were performed in two of these animals with survival of 22 and 24 days. Only two of these animals were completely T-cell depleted, and both failed to recover thymus-dependent T cells (CD4/CD45RA ). In one animal, general in vitro hyporesponsiveness was observed, with subsequent death from infection. The second animal demonstrated delayed recovery of T cells and prolonged general hyporesponsiveness in vitro. Neither animal demonstrated prolongation of porcine skin grafts compared with allografts (both rejected by day 13). CONCLUSIONS: Porcine thymic tissue is able to induce xenogeneic hyporesponsiveness. More efficient thymic engraftment may allow this approach to induce xenograft tolerance.

Animals↗
PubMed2003

Pig kidney transplantation in baboons treated intravenously with a bovine serum albumin-Galalpha1-3Gal conjugate.

The maintenance of depletion of antibody (Ab) reactive with Galalpha1-3Gal (Gal) on pig vascular endothelial cells by the intravenous (i.v.) infusion of a synthetic Gal conjugate has been proposed as a means of delaying Ab-mediated rejection of transplanted pig organs in primates. We have therefore studied the effect of the continuous i.v. infusion of bovine serum albumin conjugated to multiple synthetic Gal type 6 oligosaccharides (BSA-Gal) on anti-Gal Ab levels and on graft survival in baboons undergoing pig kidney transplantation. Group 1 baboons (n=3) underwent extracorporeal immunoadsorption of anti-Gal Ab, a cyclophosphamide (CPP)-based immunosuppressive regimen, and a non-transgenic pig kidney transplant. Group 2 (n=2) were treated identically to Group 1 but, in addition, received a continuous i.v. infusion of BSA-Gal. Group 3 (n=2) were treated identically to Group 2, but without CPP. A single baboon (Group 4) underwent extracorporeal immunoadsorption, a CPP-based regimen, and continuous i.v. BSA-Gal therapy for 28 days, but did not receive a pig kidney transplant. Two of the transplanted pig kidneys in Group 1 were excised on post transplant days 7 and 13 for a rejected ureter, and disseminated intravascular coagulation (DIC), respectively. The third baboon died of sepsis on day 6. All transplanted ureters and kidneys showed some histopathologic features of acute humoral xenograft rejection. Group 2 baboons were euthanized on days 8 and 11, respectively, for liver failure. At autopsy, there were histopathological features of widespread liver necrosis, but the pig kidneys and ureters showed no features of rejection. The pig kidneys in Group 3 baboons were excised for renal vein thrombosis (day 9) and DIC (day 12); there was no histological signs of rejection in the pig kidneys or ureter, although there were focal areas of modest liver injury in one baboon on biopsy. The single Group 4 baboon showed no biochemical or histological features of liver injury. Anti-Gal Ab levels returned in Group 1, but were maintained at negligible levels in the baboons in Groups 2 to 4 that received BSA-Gal therapy. Continuous i.v. therapy with BSA-Gal is largely successful in maintaining depletion of circulating anti-Gal antibodies and in preventing or delaying Ab deposition and acute humoral xenograft rejection in porcine grafts, but may be associated with liver injury when administered in the presence of a pig kidney transplant and CPP therapy. The mechanism of the hepatic injury remains uncertain.

Animals↗