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Jeffrey L. Platt - One of the best experts on this subject based on the ideXlab platform.
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Acute Vascular Rejection and accommodation divergent outcomes of the humoral response to organ transplantation
Transplantation, 2004Co-Authors: Josie M Williams, Zoie E Holzknecht, Timothy B Plummer, Gregory J Brunn, Shu S Lin, Jeffrey L. PlattAbstract:Background. The most difficult barrier to organ transplantation is humoral Rejection, a condition initiated by binding of antibodies to blood vessels in the graft. Fortunately, humoral Rejection is not the only outcome of antibody binding to the graft. In some cases, accommodation, a condition in which the graft does not undergo humoral injury despite the existence of humoral immunity directed against it, occurs and the graft remains seemingly inured. The mechanism underlying accommodation is uncertain, but changes in the function of antibodies, changes in the target antigen, and changes in the graft imparting resistance to injury have been implicated. Methods. Using the swine-to-baboon cardiac xenograft model, we asked which mechanism(s) may distinguish Acute Vascular Rejection from accommodation. Results. In both Acute Vascular Rejection and accommodation, antibodies were bound and complement activated in blood vessels of the graft. However, in Acute Vascular Rejection, the full complement cascade was activated; while in accommodation, the complement cascade was interrupted, suggesting complement was inhibited in the latter condition. In Acute Vascular Rejection, heparan sulfate and syndecan-4-phosphate, which can aid in complement control, were nearly absent, whereas in accommodation these were present in heightened amounts. Conclusion. These findings suggest that control of complement may underlie accommodation, at least in part, and raise the possibility that this control and possibly other protective mechanisms could be exerted by heparan sulfate.
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apoptosis and cellular activation in the pathogenesis of Acute Vascular Rejection
Circulation Research, 2002Co-Authors: Zoie E Holzknecht, Karisha L Kuypers, Timothy B Plummer, Josie Williams, Matilda Bustos, Gregory James Gores, Gregory J Brunn, Jeffrey L. PlattAbstract:Acute Vascular or humoral Rejection, a vexing outcome of organ transplantation, has been attributed by some to activation and by others to apoptosis of endothelial cells in the graft. We asked which of these processes causes Acute Vascular Rejection by tracing the processes during the development of Acute Vascular Rejection in porcine cardiac xenografts performed in baboons. Apoptosis, assayed by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL), expression of activated caspase-3, and proapoptotic genes Bax and Bcl-x L , was not detected until Acute Vascular Rejection was well advanced, and even then, apoptosis was largely confined to myocytes. Activation of the endothelium, as evidenced by expansion of rough endoplasmic reticulum and increased ribosomal antigen and phospho-p70 S6 kinase, occurred early in the course of Acute Vascular Rejection and progressed through the disease process. These findings suggest that Acute Vascular Rejection is caused by an active metabolic process and not by apoptosis in the endothelium.
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The pathology of cardiac xenografts.
Journal of Cardiac Surgery, 2001Co-Authors: Matilde Bustos, Jeffrey L. PlattAbstract:The pathology of cardiac xenografts has yielded critical insights into the mechanisms of xenograft Rejection and the therapeutic procedures that might be applied to preventing or treating it. The conditions seen in rejecting cardiac xenografts include hyperAcute Rejection, Acute Vascular Rejection, and cellular Rejection. HyperAcute and Acute Vascular Rejection of cardiac xenografts have features typical of humoral injury. Less is known about cellular Rejection and only speculation can be offered about chronic Rejection. Still, these features allow critical testing of pathogenetic mechanisms and therapies.
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Xenotransplantation and tolerance.
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2001Co-Authors: Benjamin Samstein, Jeffrey L. PlattAbstract:The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of Rejection responses. HyperAcute Rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute Vascular Rejection and cellular Rejection, however, may present important opportunities for immunological tolerance, and humoral Rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral Rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.
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the role of anti galalpha1 3gal antibodies in Acute Vascular Rejection and accommodation of xenografts
Transplantation, 2000Co-Authors: Shu S Lin, Guerard W Byrne, Lisa E Diamond, William Parker, M J Hanaway, Gonzalo V Gonzalezstawinski, Christine L Lau, Duane R Davis, John S Logan, Jeffrey L. PlattAbstract:BACKGROUND A major impediment to the transplanting of porcine organs into humans is the susceptibility of porcine organs to Acute Vascular Rejection, which can destroy a Vascularized xenograft over a period of hours to days. Acute Vascular Rejection of porcine-to-primate xenografts is thought to be triggered by binding of xenoreactive antibodies to the graft. We tested whether antibodies, binding to Galalpha1-3Gal epitopes in porcine tissue, initiate this phenomenon. METHODS AND RESULTS Specific depletion of anti-Galalpha1-3Gal antibodies from the blood of baboons, using extracorporeal perfusion of separated plasma through columns of Sepharose beads covalently linked to the antigenic trisaccharide, Galalpha1-3Galbeta1-4GlcAc, averted the development of Acute Vascular Rejection in porcine organs transgenic for human decay-accelerating factor and CD59. More importantly, after immunodepletion was stopped and Gala1-3Gal antibodies were allowed to return, these same organs continued to function and remained pathologically normal and thus seemed to achieve a state of accommodation. CONCLUSION These results demonstrate that anti-Galalpha1-3Gal antibodies cause Acute Vascular Rejection and suggest that depletion of these antibodies leads to accommodation of the donor cardiac xenograft and could supply an important model for additional study.
Norman B. Ratliff - One of the best experts on this subject based on the ideXlab platform.
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Acute Vascular Rejection is associated with up regulation of vitronectin receptor αvβ3 increased expression of tissue factor and activation of the extracellular matrix metalloproteinase induction system
Journal of Heart and Lung Transplantation, 2002Co-Authors: Mohamad H. Yamani, Randall C. Starling, Patrick M. Mccarthy, James B. Young, Daniel J. Cook, Geoffrey D Vince, Norman B. RatliffAbstract:Abstract Background A cascade of inflammatory reactions characterize Acute Vascular Rejection after heart transplantation. This study was undertaken to test the hypothesis that Acute Vascular Rejection is associated with up-regulation of vitronectin receptor (αvβ3), increased expression of tissue factor, and activation of the extracellular matrix metalloproteinase induction system. Methods Acute Vascular Rejection developed in 14 heart transplant recipients within 2 weeks of transplantation, confirmed by immunofluorescence (AVR group). We compared these patients with 10 transplant recipients who had no evidence of Acute Vascular Rejection or peritransplant ischemic injury (control group). We evaluated endomyocardial biopsy specimens for αvβ3, tissue factor, and extracellular matrix metalloproteinase inducer (EMMPRIN). Results Compared with the control group, the AVR group demonstrated evidence of significantly increased expression of αvβ3 (1.9-fold, p p p Conclusions Acute Vascular Rejection is associated with up-regulation of αvβ3, tissue factor, and activation of the matrix metalloproteinase induction system, which may contribute to the lethal morbidity associated with this disease.
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comparison of myocardial cell injury in Acute cellular Rejection versus Acute Vascular Rejection in cyclosporine treated heart transplants
Journal of Heart and Lung Transplantation, 1995Co-Authors: Sharon Hook, J F Caple, James T Mcmahon, Jonathan Myles, Norman B. RatliffAbstract:Background: Myocyte necrosis has been cited as a key feature in the diagnosis and classification of both moderate and severe Acute cellular Rejection (InternationaI Society for Heart and Lung Transplantation grades 3A to 4). However, our previous work suggests that myocyte necrosis is not a typical feature of cellular Rejection. Methods: To clarify this point and to elucidate differences between cellular Rejection and Acute Vascular Rejection, we compared the light and electron microscopic features of 35 consecutive endomyocardial biopsy specimens from six patients with Acute Vascular Rejection diagnosed with positive immunofluorescence, 12 consecutive endomyocardial biopsy specimens from three patients with mixed Acute Vascular Rejection and cellular Rejection, and 435 endomyocardial biopsy specimens of International Society for Heart and Lung Transplantation grades 2 to 4 cellular Rejection. Results: Endomyocardial biopsy specimens from eight of nine patients with Acute Vascular Rejection and mixed Acute Vascular Rejection/cellular Rejection exhibited classic myocyte necrosis as the typical form of myocardial cell injury. Myocyte necrosis was characterized by lysis of the sarcolemma, marked swelling of mitochondria, and intramitochondrial flocculent densities. In contrast, the typical form of myocardial cell injury in cellular Rejection was reversible. Reversible cellular Rejection was characterized by extensive loss of myosin filaments and Z-lines with subsarcolemmal and intracytoplasmic accumulation of Z-band material. Cell swelling, mitochondrial swelling, intramitochondrial densities, and lysis of sarcolemma were not observed. Conclusions: We conclude that myocyte necrosis is a characteristic feature of Acute Vascular Rejection, whereas reversible myocardial cell injury is characteristic of cellular Rejection, including grade 4. Myocyte necrosis is not a feature of cellular Rejection. The presence of true myocyte necrosis in endomyocardial biopsy specimens from cyclosporine-treated heart transplants implicates some process other than cellular Rejection. Processes producing myocyte necrosis include Acute Vascular Rejection, peritransplantation ischemia, and accelerated atherosclerosis
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activation of intraVascular macrophages within myocardial small vessels is a feature of Acute Vascular Rejection in human heart transplants
Journal of Heart and Lung Transplantation, 1995Co-Authors: Norman B. Ratliff, J T McmahonAbstract:Background: We investigated the pathogenesis of Acute Vascular Rejection by performing immunofluorescent screening on frozen sections for C1q, C3c, and immunoglobulin M in endomyocardial biopsy specimens from all new heart transplants. Methods: Immunofluorescence for C4c, C5, immunoglobulin G, and immunoglobulin A was performed on all positive endomyocardial biopsy specimens. Twenty-eight positive endomyocardial biopsy specimens from six patients were identified, and 22 of those were studied with transmission electron microscopy. Results: Endothelial hyperplasia and myocyte necrosis were prominent in the five female patients with positive immunofluorescence. In addition, macrophages with ultrastructural cytologic features of activation were seen filling capillaries and venules in intimate contact with endothelium and exiting those vessels. Activated macrophages were large cells with abundant cytoplasm and ruffled borders and contained numerous lysosomes, rough endoplasmic reticulum, and mitochondria. IntraVascular activated macrophages were identified in five of six patients with positive immunofluorescence but were not seen in any of the endomyocardial biopsy specimens with negative immunofluorescence, including multiple examples of moderate (grades 2 to 3B) and severe (grade 4) Acute cellular Rejection. In the five female patients with activated macrophages, Acute Vascular Rejection recurred multiple times with one fatality. Review of the files showed three additional, similar cases. The one male patient with positive immunofluorescence but without activated macrophages had only a single episode of Acute Vascular Rejection. Conclusions: Complement and antibodies can activate macrophages, so this finding is not surprising. To the best of our knowledge, this is the first report of the intraVascular activation of macrophages, and the first association of this process with Acute Vascular Rejection. Activated macrophages may contribute to myocyte necrosis in Acute Vascular Rejection by compromising blood flow in small vessels
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Acute Vascular humoral Rejection in non okt3 treated cardiac transplants
Cardiovascular Pathology, 1995Co-Authors: Jocelyn Field Caple, James T Mcmahon, Sharon Hook, Jonathan Myles, Norman B. RatliffAbstract:To determine the incidence and morphologic features of Acute Vascular Rejection (AVR) in cardiac transplant patients who have not received OKT3 induction therapy, we performed immunofluorescence (IF) staining for Clq and C3c on 341 endomyocardial biopsies from 135 patients. Each AVR biopsy, defined by positive IF, was further evaluated for C4c, C5, IgG, IgM, and IgA. Light and electron microscopy were also performed. The clinical features of each case were reviewed. A total of 29 biopsies from 6 recently transplanted patients (1993) and 10 biopsies from 4 long-term transplants (pre-1993) had IF evidence of AVR. All patients with AVR had linear Vascular deposits of various complement components and immunoglobulins. Of the 6 recently transplanted patients, 4 were multiparous females. The male had a single episode of AVR. IF patterns were variable between and within patients. Clq and C3c were the most consistently detected complement components. IgM was the most frequently detected antibody. Of the 10 cases of AVR, 6 occurred within the first month post-transplant. Myocyte necrosis was present in all cases with cardiac dysfunction. Patients with early onset AVR had more recurrences and one fatality. There was one fatality in the long-term transplant group. Concomitant grades 0 to 4+ cellular Rejection did not correlate with results of IF or clinical severity. The incidence of AVR in non-OKT3-treated patients is 7%. Of the early onset patients, 66% are multiparous females, indicating the possible importance of prior sensitization. IF patterns are not predictive of outcome. AVR may be asymptomatic, but early onset predicts a difficult clinical course and is detected only by IF screening.
David R Grant - One of the best experts on this subject based on the ideXlab platform.
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endothelial induction of fgl2 contributes to thrombosis during Acute Vascular xenograft Rejection
Journal of Immunology, 2004Co-Authors: Anand Ghanekar, Robert Zhong, Michael Mendicino, Mingfeng Liu, Hao Liu, James M Phillips, Gary A Levy, David R GrantAbstract:Thrombosis is a prominent feature of Acute Vascular Rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the Vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft Vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-α in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2 +/+ and fgl2 +/− mice into Lewis rats developed AVR with intraVascular thrombosis associated with induction of fgl2 in graft Vascular ECs. In contrast, xenografts from fgl2 −/− mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the Vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.
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rat to mouse small bowel xenotransplantation a novel model for studying Acute Vascular and hyperAcute xenograft Rejection and xenogenic cell migration
Xenotransplantation, 1999Co-Authors: Hidenori Kiyochi, Robert Zhong, Bertha Garcia, Richard Kellersmann, Anna Blomer, Zheng Zhang, David R GrantAbstract:Kiyochi H, Kellersmann R, Blomer A, Garcia BM, Zhang Z, Zhong R and Grant DR. Rat-to-mouse small bowel xenotransplantation: A novel model for studying Acute Vascular and hyperAcute xenograft Rejection and xenogenic cell migration. Xenotransplantation 1999; 6: 00-00. ©Munksgaard, Copenhagen Abstract: The present study was undertaken to establish a rat-to-mouse Vascularized small bowel xenotransplantation model to study Acute Vascular and hyperAcute xenograft Rejection, and xenogenic cell migration. Lewis rat small bowel grafts were transplanted heterotopically to group 1, Balb/c mice, and group 2, Balb/c mice pre-sensitized with a donor spleen cell injection. The grafts were examined by serial pathology and flow cytometry. In group 1, Acute Vascular Rejection was present by the 5th post-operative day (POD). Immunohistology showed a strong endothelial deposition of IgG, IgM and C3, associated with a minimal lymphocytic infiltrate. There was a vigorous cell migration from the recipient to the graft, in which recipient origin cells comprised 80.1± 6.9% of the graft mesenteric lymph node by POD 3. However, there was almost no cell migration from the graft to the recipient. The intestinal xenografts in the group 2 showed massive hemorrhage, fibrin deposition, Vascular congestion and thrombosis 60 min after transplantation. IgG and C3 were present on the endothelium as early as 1 min after reperfusion. The vigorous humorally-mediated Vascular damage and rapid elimination of donor cells seen with intestinal xenograft Rejection are distinct from the usual picture of allograft Rejection. HyperAcute Rejection can be induced by recipient pre-sensitization with donor spleen cells. The potential advantages of studying xenotransplantation in this model include: (1) the wide range of immunologic reagents available for mice; (2) the opportunity to study the progression of Vascular damage easily by performing serial biopsies in the same animal; and (3) the opportunity to study, in vivo, two-way cellular response by examining cell trafficking in the mesenteric lymph nodes.
Timothy B Plummer - One of the best experts on this subject based on the ideXlab platform.
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Acute Vascular Rejection and accommodation divergent outcomes of the humoral response to organ transplantation
Transplantation, 2004Co-Authors: Josie M Williams, Zoie E Holzknecht, Timothy B Plummer, Gregory J Brunn, Shu S Lin, Jeffrey L. PlattAbstract:Background. The most difficult barrier to organ transplantation is humoral Rejection, a condition initiated by binding of antibodies to blood vessels in the graft. Fortunately, humoral Rejection is not the only outcome of antibody binding to the graft. In some cases, accommodation, a condition in which the graft does not undergo humoral injury despite the existence of humoral immunity directed against it, occurs and the graft remains seemingly inured. The mechanism underlying accommodation is uncertain, but changes in the function of antibodies, changes in the target antigen, and changes in the graft imparting resistance to injury have been implicated. Methods. Using the swine-to-baboon cardiac xenograft model, we asked which mechanism(s) may distinguish Acute Vascular Rejection from accommodation. Results. In both Acute Vascular Rejection and accommodation, antibodies were bound and complement activated in blood vessels of the graft. However, in Acute Vascular Rejection, the full complement cascade was activated; while in accommodation, the complement cascade was interrupted, suggesting complement was inhibited in the latter condition. In Acute Vascular Rejection, heparan sulfate and syndecan-4-phosphate, which can aid in complement control, were nearly absent, whereas in accommodation these were present in heightened amounts. Conclusion. These findings suggest that control of complement may underlie accommodation, at least in part, and raise the possibility that this control and possibly other protective mechanisms could be exerted by heparan sulfate.
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apoptosis and cellular activation in the pathogenesis of Acute Vascular Rejection
Circulation Research, 2002Co-Authors: Zoie E Holzknecht, Karisha L Kuypers, Timothy B Plummer, Josie Williams, Matilda Bustos, Gregory James Gores, Gregory J Brunn, Jeffrey L. PlattAbstract:Acute Vascular or humoral Rejection, a vexing outcome of organ transplantation, has been attributed by some to activation and by others to apoptosis of endothelial cells in the graft. We asked which of these processes causes Acute Vascular Rejection by tracing the processes during the development of Acute Vascular Rejection in porcine cardiac xenografts performed in baboons. Apoptosis, assayed by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL), expression of activated caspase-3, and proapoptotic genes Bax and Bcl-x L , was not detected until Acute Vascular Rejection was well advanced, and even then, apoptosis was largely confined to myocytes. Activation of the endothelium, as evidenced by expansion of rough endoplasmic reticulum and increased ribosomal antigen and phospho-p70 S6 kinase, occurred early in the course of Acute Vascular Rejection and progressed through the disease process. These findings suggest that Acute Vascular Rejection is caused by an active metabolic process and not by apoptosis in the endothelium.
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expression of tissue factor mrna in cardiac xenografts clues to the pathogenesis of Acute Vascular Rejection
Transplantation, 2000Co-Authors: T Nagayasu, Timothy B Plummer, Soheyla Saadi, Robert A Holzknecht, Jeffrey L. PlattAbstract:Background. Acute Vascular Rejection destroys Vascularized xenografts over a period of hours to days and is now considered the major hurdle to the clinical application of xenotransplantation. The hallmark of Acute Vascular Rejection is diffuse intraVascular coagulation; however, the pathogenesis of coagulation is a matter of controversy. One line of evidence points to activated endothelial cells and another to activated inflammatory cells as a source of tissue factor and thus as a primary cause of this lesion. The distinction between the two mechanisms inducing coagulation in the xenograft provides an opportunity for specific intervention. Methods. To explore these mechanisms, we studied the expression of tissue factor mRNA by in situ reverse transcriptase-polymerase chain reaction in relation to the histopathologic manifestations of Acute Vascular Rejection in guinea pig hearts transplanted into rats treated by cobra venom factor to avoid the hyperAcute Rejection. Results. Three hours after transplantation and before the deposition of fibrin, tissue factor mRNA was expressed in the endothelial cells lining small and medium blood vessels and in smooth muscle cells of guinea pig cardiac xenografts. Sixteen hours after transplantation, while rat tissue factor mRNA was expressed only in occasional infiltrating cells, cardiac xenografts showed prominent deposits of fibrin in small vessels. Maximum expression of tissue factor on rat infiltrating cells was observed 48 hr after transplantation. Conclusions. These results suggest that in Acute Vascular Rejection, coagulation is initiated on the donor Vascular system, while the procoagulant characteristics of infiltrating cells may reflect a response to tissue injury rather than a cause.
Robert Zhong - One of the best experts on this subject based on the ideXlab platform.
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prevention of Acute Vascular Rejection by a functionally blocking anti c5 monoclonal antibody combined with cyclosporine
Transplantation, 2005Co-Authors: H Wang, Robert Zhong, Bertha Garcia, Weihua Liu, Jifu Jiang, Dalibor Kubelik, Gang Chen, David Gies, Russell P RotherAbstract:Background. Inhibition of the complement cascade at C5 prevents formation of pro-inflammatory molecules C5a and C5b-9, which play a key role in allograft Rejection. The present study was undertaken to determine whether blocking terminal complement with anti-C5 monoclonal antibody (mAb) alone or combined with cyclosporine (CsA) would prevent Acute Vascular Rejection (AVR) in a mouse cardiac allograft model. Methods. C3H mouse hearts were transplanted into BALB/c mice and randomized into five groups with the following treatments: (1) no treatment; (2) CsA alone; (3) control mAb; (4) anti-C5 mAb alone; and (5) anti-C5 mAb and CsA. Results. Allografts in untreated or control mAb-treated recipients were rapidly rejected at 8.0±0.6 and 8.2±0.8 days, respectively. These grafts exhibited typical AVR, characterized by vasculitis, hemorrhage, and thrombosis. A high level of complement activity was also demonstrated in these animals. High-dose CsA was not able to inhibit complement activation or AVR, and grafts were rejected in 15.5±1.1 days. Anti-C5 monotherapy completely inhibited complement activation and attenuated AVR, but grafts were rejected in 8.3 ±0.5 days by Acute cellular Rejection. In contrast, a combination of anti-C5 mAb and CsA successfully achieved indefinite graft survival (>100 days). This combined therapy completely inhibited terminal complement activation and prevented both humoral- and cellular-mediated Rejection. Conclusions. Combination therapy of anti-C5 mAb and CsA achieves indefinite graft survival in a mouse cardiac allograft model. These data suggest that inhibition of terminal complement using anti-C5 mAb may be an effective therapeutic adjunct to prevent AVR in clinical transplantation.
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Current advances in xenotransplantation.
Hepatobiliary & pancreatic diseases international : HBPD INT, 2005Co-Authors: Ashley R Cox, Robert ZhongAbstract:BACKGROUND: Transplantation of organs is a well-known and accepted life-saving procedure for end-stage kidney, liver, heart and lung diseases. The insufficient number of donor organs limits the application of this technique and leads to unnecessary loss of life. Experimental techniques such as xenotransplantation are extremely important to determine new methods of creating organ availability. DATA SOURCES: A literature search of Pubmed database was conducted and research articles reviewed. RESULTS: Xenotransplantation is a progressive field of research. Human complement regulatory protein (hDAF) transgenic pigs and new immunosuppressive strategies that reduce xenoreactive αgal antibodies, have decreased rates of Acute Vascular Rejection. Transplantation of α-1, 3-galac-tosyltransferase knock-out pig organs into baboons has resulted in the longest graft survival to date. Coagulation pathways have been identified as having a role in graft Rejection. In vitro studies of porcine endogenous retroviruses (PERVs) show encouraging results that zoonosis will be less hindering to xenotransplantation than once thought. CONCLUSIONS: Several recent advances in xenotransplantation research have brought this technique closer to clinical application. The Ethics Committee of the International Xenotransplantation Association has made recommendations to ensure maintenance, of ethical standards. Advancement will depend on the development of pig models novel immunosuppressive strategies to target the innate immune system, and new ways to create donor specific tolerance. Prevention of Rejection and transmission of Infectious agents remain unresolved issues. In the future, it is feasible that xenotransplantation will be used to resolve this medical dilemma.
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endothelial induction of fgl2 contributes to thrombosis during Acute Vascular xenograft Rejection
Journal of Immunology, 2004Co-Authors: Anand Ghanekar, Robert Zhong, Michael Mendicino, Mingfeng Liu, Hao Liu, James M Phillips, Gary A Levy, David R GrantAbstract:Thrombosis is a prominent feature of Acute Vascular Rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the Vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft Vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-α in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2 +/+ and fgl2 +/− mice into Lewis rats developed AVR with intraVascular thrombosis associated with induction of fgl2 in graft Vascular ECs. In contrast, xenografts from fgl2 −/− mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the Vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.
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The axis of interleukin 12 and gamma interferon regulates Acute Vascular xenogeneic Rejection
Nature Medicine, 2000Co-Authors: Hao Wang, Mark E. Devries, Bertha Garcia, Shaoping Deng, Masud H. Khandaker, J. Geoff Pickering, Larry H. Chow, David J. Kelvin, Robert ZhongAbstract:Recent advances using transgenic animals or exogenous complement inhibitors have demonstrated prevention of hyperAcute Rejection of Vascularized organs, but not graft loss due to Acute Vascular Rejection. Using various wild-type and cytokine-deficient mice strains, we have examined the mechanisms of Acute Vascular Rejection. C57BL/6 mice deficient in interleukin12 or gamma interferon showed faster Acute Vascular Rejection than did wild-type mice. Furthermore, mice defective in B-cell development showed no Acute Vascular Rejection. These results demonstrate that the axis of interleukin 12 and gamma interferon provides a survival advantage in Vascularized xenografts by delaying or preventing Acute Vascular Rejection caused by a B cell-dependent mechanism.
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rat to mouse small bowel xenotransplantation a novel model for studying Acute Vascular and hyperAcute xenograft Rejection and xenogenic cell migration
Xenotransplantation, 1999Co-Authors: Hidenori Kiyochi, Robert Zhong, Bertha Garcia, Richard Kellersmann, Anna Blomer, Zheng Zhang, David R GrantAbstract:Kiyochi H, Kellersmann R, Blomer A, Garcia BM, Zhang Z, Zhong R and Grant DR. Rat-to-mouse small bowel xenotransplantation: A novel model for studying Acute Vascular and hyperAcute xenograft Rejection and xenogenic cell migration. Xenotransplantation 1999; 6: 00-00. ©Munksgaard, Copenhagen Abstract: The present study was undertaken to establish a rat-to-mouse Vascularized small bowel xenotransplantation model to study Acute Vascular and hyperAcute xenograft Rejection, and xenogenic cell migration. Lewis rat small bowel grafts were transplanted heterotopically to group 1, Balb/c mice, and group 2, Balb/c mice pre-sensitized with a donor spleen cell injection. The grafts were examined by serial pathology and flow cytometry. In group 1, Acute Vascular Rejection was present by the 5th post-operative day (POD). Immunohistology showed a strong endothelial deposition of IgG, IgM and C3, associated with a minimal lymphocytic infiltrate. There was a vigorous cell migration from the recipient to the graft, in which recipient origin cells comprised 80.1± 6.9% of the graft mesenteric lymph node by POD 3. However, there was almost no cell migration from the graft to the recipient. The intestinal xenografts in the group 2 showed massive hemorrhage, fibrin deposition, Vascular congestion and thrombosis 60 min after transplantation. IgG and C3 were present on the endothelium as early as 1 min after reperfusion. The vigorous humorally-mediated Vascular damage and rapid elimination of donor cells seen with intestinal xenograft Rejection are distinct from the usual picture of allograft Rejection. HyperAcute Rejection can be induced by recipient pre-sensitization with donor spleen cells. The potential advantages of studying xenotransplantation in this model include: (1) the wide range of immunologic reagents available for mice; (2) the opportunity to study the progression of Vascular damage easily by performing serial biopsies in the same animal; and (3) the opportunity to study, in vivo, two-way cellular response by examining cell trafficking in the mesenteric lymph nodes.