Acute Vascular Rejection - Explore the Science & Experts | ideXlab

Acute Vascular Rejection and accommodation divergent outcomes of the humoral response to organ transplantation

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.

apoptosis and cellular activation in the pathogenesis of Acute Vascular Rejection

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.

The pathology of cardiac xenografts.

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.

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

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.

comparison of myocardial cell injury in Acute cellular Rejection versus Acute Vascular Rejection in cyclosporine treated heart transplants

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

activation of intraVascular macrophages within myocardial small vessels is a feature of Acute Vascular Rejection in human heart transplants

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

endothelial induction of fgl2 contributes to thrombosis during Acute Vascular xenograft Rejection

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.

rat to mouse small bowel xenotransplantation a novel model for studying Acute Vascular and hyperAcute xenograft Rejection and xenogenic cell migration

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.