Model Of Chronic Rejection Research Articles

Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection

Ischemia/reperfusion injury may have deleterious short- and long-term consequences for cardiac allografts. The underlying mechanisms involve microvascular dysfunction that may culminate in primary graft failure or untreatable chronic rejection. Here, we report that rat cardiac allograft ischemia/reperfusion injury resulted in profound microvascular dysfunction that was prevented by donor treatment with peroral single-dose simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase and Rho GTPase inhibitor, 2 hours before graft procurement. During allograft preservation, donor simvastatin treatment inhibited microvascular endothelial cell and pericyte RhoA/Rho-associated protein kinase activation and endothelial cell-endothelial cell gap formation; decreased intragraft mRNA levels of hypoxia-inducible factor-1α, inducible nitric oxide synthase, and endothelin-1; and increased heme oxygenase-1. Donor, but not recipient, simvastatin treatment prevented ischemia/reperfusion injury-induced vascular leakage, leukocyte infiltration, the no-reflow phenomenon, and myocardial injury. The beneficial effects of simvastatin on vascular stability and the no-reflow phenomenon were abolished by concomitant nitric oxide synthase inhibition with N-nitro-l-arginine methyl ester and RhoA activation by geranylgeranyl pyrophosphate supplementation, respectively. In the chronic rejection model, donor simvastatin treatment inhibited cardiac allograft inflammation, transforming growth factor-β1 signaling, and myocardial fibrosis. In vitro, simvastatin inhibited transforming growth factor-β1-induced microvascular endothelial-to-mesenchymal transition. Our results demonstrate that donor simvastatin treatment prevents microvascular endothelial cell and pericyte dysfunction, ischemia/reperfusion injury, and chronic rejection and suggest a novel, clinically feasible strategy to protect cardiac allografts.

Interleukin-33 prolongs allograft survival during chronic cardiac rejection

Interleukin-33 (IL-33) stimulates the generation of cells and cytokines characteristic of a Th2 immune response. We examined the effects of IL-33 on allografted heart tissue in a chronic cardiac rejection model, including analysis of the peripheral myeloid and lymphoid compartments. B6.C-H2bm12/KhEg hearts were transplanted into MHC class II-mismatched C57Bl/6J mice; IL-33 was administered daily. Cells from allografts and spleens were isolated for flow cytometry and cultured for cytokine production; some tissues were used for immunohistochemistry. Animals treated with IL-33 showed significantly longer allograft survival, which was associated with a distinct cytokine profile produced by graft-infiltrating cells. Proinflammatory IL-17A production was decreased with IL-33 treatment, while increased levels of IL-5, IL-10, and IL-13 were observed. After IL-33 therapy, flow cytometry showed a direct induction of CD4(+) Foxp3(+) Treg, whereas the number of B220(+) CD19(+) B cells, and circulating, as well as allograft deposited, alloantibodies was reduced. Following IL-33 treatment, a significant decrease in graft-infiltrating CD11b(high) Gr1(high) granulocytes coincided with a significant increase in CD11b(high) Gr1(intermediate) myeloid-derived suppressor cells (MDSC). In conclusion, IL-33 treatment in the setting of chronic rejection promotes the development of a Th2-type immune response that favors MDSC and Treg expansion, reduces antibody-mediated rejection (AMR), and ultimately, prolongs allograft survival.

Depletion of FoxP3+T-cells enhances anti-MHC class I induced autoimmunity in FoxP3DTR transgenic murine model: role in pathogenesis of chronic rejection (115.12)

Abstract Recent evidence strongly suggest that alloimmunity induced autoimmune process plays an important role in the development of chronic rejection following human lung transplantation. We have previously shown that intrabronchial administration of MHC Class I antibodies (Abs) to mice causes obliterative airway disease (OAD, which is considered as a model for chronic rejection following human lung transplantation. Our goal is to study the impact of FoxP3+ regulatory T-cells (Tregs) in this established murine model of OAD. FoxP3DTR transgenic Bl/6 mice (kindly provided by Dr. Rudensky), following diphtheria toxin (DT) administration the Treg frequency at 48hrs decreased by 98%. Intrabronchial administration of H2Kb Abs into DT treated mice demonstrated a 3 fold increase in airway lesions and fibrous deposition over non-Treg depleted animals. Antibody concentrations to self antigens increased from 154 ± 32 to 265 ± 48 µg/mL for Collagen-V and 243 ± 43 to 394 ± 48 µg/mL for K- α1Tubulin. ELISpot analysis for Th-precursor frequency showed enhanced levels of IFN-γ (2.3 fold), IL-17 (3.3 fold) and decreased levels of IL-10 (4.1 fold) in Treg depleted cohort. RT-PCR analysis on lung tissue demonstrated upregulation of chemokines and pro-fibrotic growth factors in Treg depleted cohort. We conclude that depletion of T reg increases the severity of OAD as well as development of autoimmune responses to self-antigens leading to pathogenesis of chronic rejection.

KCa3.1 as a potential new target for the prevention of chronic allograft vasculopathy and airway allograft rejection

The Ca+-activated K+ channel KCa3.1 is critically involved in the activation of T cells, macrophages, proliferating vascular smooth muscle cells and fibroblasts. KCa3.1 has therefore been suggested as a potential therapeutic target for diseases where activation and excessive proliferation of one or more of these cell types is involved in the pathology. We here evaluated the KCa3.1 blocker TRAM-34 in two models of chronic allograft rejection. In an obliterative airway disease model, where tracheas from CBA mice were heterotopically transplanted into the greater omentum of C57Bl6 mice, both genetic deficiency and pharmacological blockade of KCa3.1 with TRAM-34 reduced luminal obliteration and significantly suppressed IFN-gamma and IL4 in Elispot assays. We further performed orthotopic aortic transplantations in the PVG-to-ACI rat model and evaluated chronic allograft vasculopathy after 120 days. TRAM-34 dose-dependently reduced aortic luminal occlusion, adventitia area and mononuclear cell infiltration. Its effectiveness was comparable to the m-Tor inhibitor rapamycin (0.3 mg/kg). Our findings suggest that KCa3.1 channels are involved in the pathology of obliterative airway disease, a major complication after lung-transplantation, and chronic allograft vasculopathy, which remains one the major obstacles to long-term functioning of solid organ transplants. Supported by NIH (RO1GM076063)

Establishment of a Chronic Rejection Model for Orthotopic Liver Transplantation in the Rat

Background: This study aims to establish a stable chronic rejection model for orthotopic liver transplantation in the rat and to describe the pathological features of this model. Methods: The livers from different strains of rats were transplanted in various allogeneic donor-recipient combinations with appropriate syngeneic grafts used as controls. The rats were untreated after surgery (acute rejection model) or treated with cyclosporin A (1 mg/kg) and hydrocortisone (0.75 mg/kg) to establish chronic rejection as determined by rejection activity index scores from pathological examination of liver specimens. Results: Acute rejection occurred in all of the untreated recipients of allogeneic orthotopic liver transplants, and all died within 30 days. Among the treated recipients, the combinations of Lewis with brown Norway and dark agouti with Lewis rats developed acute rejection, and no changes characteristic of chronic rejection were observed in the few rats that survived beyond 30 days. In contrast, the treated Lewis recipients of livers from Sprague-Dawley rats exhibited chronic rejection in the liver specimens. Conclusion: We have established an animal model for chronic rejection after transplantation of livers from Sprague-Dawley to Lewis rats under short-term immunosuppression induced by small doses of cyclosporin A and hydrocortisone.

Orthotopic Aortic Transplantation: A Rat Model to Study the Development of Chronic Vasculopathy

Research models of chronic rejection are essential to investigate pathobiological and pathophysiological processes during the development of transplant vasculopathy (TVP). The commonly used animal model for cardiovascular chronic rejection studies is the heterotopic heart transplant model performed in laboratory rodents. This model is used widely in experiments since Ono and Lindsey published their technique. To analyze the findings in the blood vessels, the heart has to be sectioned and all vessels have to be measured. Another method to investigate chronic rejection in cardiovascular questionings is the aortic transplant model. In the orthotopic aortic transplant model, the aorta can easily be histologically evaluated. The PVG-to-ACI model is especially useful for CAV studies, since acute vascular rejection is not a major confounding factor and Cyclosporin A (CsA) treatment does not prevent the development of CAV, similar to what we find in the clinical setting. A7-day period of CsA is required in this model to prevent acute rejection and to achieve long-term survival with the development of TVP. This model can also be used to investigate acute cellular rejection and media necrosis in xenogeneic models.

Extra cellular matrix remodelling after heterotopic rat heart transplantation: gene expression profiling and involvement of ED-A+ fibronectin, alpha-smooth muscle actin and B+ tenascin-C in chronic cardiac allograft rejection

Chronic cardiac rejection is represented by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) known to cause severe complications. These processes are accompanied by remarkable changes in the cardiac extra cellular matrix (cECM). The aim of our study was to analyse the cECM remodelling in chronic rejection and to elucidate a potential role of ED-A domain containing fibronectin (ED-A(+) Fn), alpha smooth muscle actin (ASMA) and B domain containing tenascin-C (B(+) Tn-C). A model of chronic rejection after heterotopic rat heart transplantation was used. Allografts, recipient and control hearts were subjected to histological assessment of rejection grade, to real-time PCR based analysis of 84 genes of ECM and adhesion molecules and to immunofluorescence labelling procedures, including ED-A(+) Fn, ASMA and B(+) Tn-C antibodies. Histological analysis revealed different grades of chronic rejection. By gene expression analysis, a relevant up-regulation of the majority of ECM genes in association with chronic rejection could be shown. For 8 genes, there was a relevant up-regulation in allografts as well as in the corresponding recipient hearts. Association of ASMA positive cells with the grade of chronic rejection could be proven. In CAV and also in CIF there were extensive co-depositions of ED-A(+) Fn, ASMA and B(+) Tn-C. In conclusion, chronic cardiac allograft rejection is associated with a cECM remodelling. ASMA protein deposition in CAV, and CIF is a valuable marker to detect chronic rejection. Interactions of VSMCs and Fibro-/Myofibroblasts with ED-A(+) Fn and B(+) Tn-C might functionally contribute to the development of chronic cardiac rejection.

The establishment of chronic rejection model of rat's aortic transplantation

Objective To establish an aortic transplantation model in the rat. Methods A thoracic aorta to abdominal aorta interposition transplant model in the rat was established. The male Lewis rats were used as donors and the female Brown Norway(BN) rats were used as recipients.Intercepted the thoracic aorta of lewis rats about one and a half centimeter. Transplanted it on the abdominal aorta of BN rats. The activity and weight change of BN rats were observed everyday until 1 week after transplantation. Then observed these index one time a week. The transplanted aortas were harvested at 8 weeks after transplantation. The intimal thickening were observed by pathological. The expression of CD3,CD68 and α-actin on transplanted aorta were observed by immunohistochemistry. Resuts All operations were finished within 2 hours. No recipients died during operation. All recipients could survival more than 8 weeks. The symptoms of bowing back, hair shedding and weight loss was appeared after transplantation. The weight of the rats were upturn at 4 or 5 days after transplantation. About 1 week after transplantation, all situations of the rats were recovery to the lever before transplantation. 8 weeks after transplantation the intimal thickening of the transplanted aortas were observed obviously by pathological. And the expressions of CD3, CD68 and α-actin on aortic allograft were observed. Conclusion The intimal thickening and the expressions of CD3, CD68 and α-actin on aortic allograft were typical expressions of chronic rejection. So this aortic transplantation model is feasible and reliable for studying chronic rejection. Key words: Aorta; Vessel transplantation; Allograft rejection; Animal model

Cardiomyocyte-targeted HIF-1α gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat

Hypoxia-inducible factor-1 (HIF-1), a key transcription factor in hypoxia, affects a wide range of adaptive cell functions. We examined the kinetics of endogenous HIF-1alpha during acute and chronic rejection, and the effect of exogenous HIF-1alpha in chronically rejecting rat cardiac allografts. Heterotopic cardiac transplantations were performed between major MHC-mismatched Dark Agouti and Wistar-Furth rats. Cyclosporine A (CsA) was used to prevent acute rejection in the chronic rejection model. The effect of HIF-1alpha overexpression was investigated by adeno-assocated virus 2 (AAV2)-mediated gene transfer of a constitutively stabilized form of mouse HIF-1alpha (AAV-HIF-1alpha). The analysis of allografts was based on histology, immunohistochemistry and quantitative reverse transcript-polymerase chain reaction (RT-PCR). Acute and chronic rejection significantly induced HIF-1alpha mRNA in rat cardiac allografts when compared with syngeneic controls. Immunohistochemistry localized significantly increased HIF-1alpha immunoreactivity to vascular smooth muscle cells, vascular endothelial cells, post-capillary venules and graft-infiltrating mononuclear inflammatory cells of the allograft, whereas expression in cardiomyocytes remained unchanged. Regression analysis revealed a linear correlation between the progression of cardiac allograft vasculopathy (CAV) and HIF-1alpha immunoreactivity in post-capillary venules and graft-infiltrating mononuclear inflammatory cells in chronically rejecting rat cardiac allografts. AAV-HIF-1alpha enhanced cardiomyocyte HIF-1alpha production and significantly reduced cardiomyocyte apoptosis and the development of CAV in chronically rejecting rat cardiac allografts. We found that acute and chronic rejection increased HIF-1alpha mRNA and protein levels in rat cardiac allografts. On the other hand, cardiomyocyte-targeted HIF-1alpha gene transfer inhibited cardiomyocyte apoptosis and the development of CAV, suggesting a novel therapeutic strategy for HIF-1alpha in cardiac allografts.

Expression of Phosphatidylserine-Specific Phospholipase A1 mRNA in Human THP-1-Derived Macrophages

The expression of phosphatidylserine-specific phospholipase A(1) (PS-PLA(1)) is most upregulated in the genes of peripheral blood cells from chronic rejection model rats bearing long-term surviving cardiac allografts. The expression profile of PS-PLA(1) in peripheral blood cells responsible for the immune response may indicate a possible biological marker for rejection episodes. In this study, PS-PLA(1) mRNA expression was examined in human THP-1-derived macrophages. The effects of several immunosuppressive agents on this expression were also examined in in vitro experiments. A real-time RT-PCR analysis revealed that PS-PLA(1) mRNA expression was found in human THP-1-derived macrophages. This expression was enhanced in the cells stimulated with lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. Other TLR ligands (TLR2, 3, 5, 7, and 9) did not show a significant induction of PS-PLA(1) mRNA. The time course of the mRNA expression profiles was different between PS-PLA(1) and tumor necrosis factor-α (TNF-α), which showed a maximal expression at 12 and 1 h after LPS stimulation, respectively. Among the observed immunosuppressive agents, corticosteroids, prednisolone, 6α-methylprednisolone, dexamethasone, and beclomethasone inhibited PS-PLA(1) expression with half-maximal inhibitory concentrations less than 3.0 nM, while methotrexate, cyclosporine A, tacrolimus, 6-mercaptopurine, and mycophenoic acid showed either a weak or moderate inhibition. These results suggest that the expression of PS-PLA(1) mRNA in THP-1-derived macrophages is activated via TLR4 and it is inhibited by corticosteroids, which are used at high dosages to suppress chronic allograft rejection.

Paradoxical Functions of B7: CD28 Costimulation in a MHC Class II-Mismatched Cardiac Transplant Model

Blockade of the B7: CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, this pathway has also been demonstrated to be important for the generation and maintenance of regulatory T cells. In this study, we investigated the role of the B7: CD28 pathway in the 'bm12 into B6' MHC class II-mismatched vascularized cardiac transplant model of chronic rejection. Allograft rejection was remarkably accelerated in B6 background B7DKO and CD28KO recipients compared with B6 wild-type (WT) recipients. Allograft rejection was associated with a significantly enhanced Th1/Th2 alloreactivity and marked reduction in the ratio of regulatory T cells to CD4(+) effector/memory cells. We noted that administration of anti-B7-1 and anti-B7-2 mAb prior to transplantation also accelerated allograft rejection. Furthermore, depleting CD25(+) cells in B6 WT recipients of bm12 hearts prior to transplant also precipitated rejection at a similar rate. Neither B7/CD28 deficiency nor CD25 depletion affected graft survival in single MHC class I-mismatched (bm1 into B6) recipients. This study highlights the paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched model, in which the B7: CD28 pathway is demonstrated to be important in preventing rejection through the generation and maintenance of Tregs.

A model of chronic lung allograft rejection in the rat

Bronchiolitis obliterans, the pathological hallmark of chronic pulmonary rejection, severely impacts long-term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporary in vivo models. Here, a model of chronic rejection is described, with sensitised recipients receiving unilateral orthotopic rat lung transplants. Lewis rats, sensitised with skin from brown Norway rats 7 days before receiving left lung transplants from donors that were Lewis x brown Norway F(1) hybrids, were analysed during day 21-84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporin, and characterised histologically, immunohistochemically and by reverse transcriptase PCR. Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles, with strong expression of smooth muscle alpha-actin and upregulation of mRNA for T-helper cell type-1 cytokines, smooth muscle alpha-actin, transforming growth factor-beta and CC chemokine ligand 5, but decreased forkhead box protein P3 gene expression. A reproducible and clinically relevant experimental set-up for progressive chronic rejection in rat pulmonary allografts is described. This model will permit better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as an in vivo set-up for testing the efficacy of novel therapeutic interventions.

The role of recipient mast cells in acute and chronic cardiac allograft rejection in C57BL/6-KitW-sh/W-sh mice

Mast cells are hypothesized to promote rejection and adverse remodeling in cardiac allografts. In contrast, it has been reported that mast cells may enhance cardiac allograft survival in rats. We used C57BL/6-Kit(W-sh/W-sh) mast cell-deficient and corresponding wild-type mice to investigate possible contributions of recipient mast cells to acute or chronic cardiac allograft rejection. FVB (H-2(q); acute rejection), or C-H-2(bm12)KhEg (H-2(bm12); chronic rejection) donor hearts were heterotopically transplanted into C57BL/6-Kit(W-sh/W-sh) (H-2(b)) or C57BL/6-Kit(+/+) (H-2(b)) mice. The degree of acute rejection was assessed at 5 days and chronic rejection, at 52 days. In the acute rejection model, donor heart vascular cell adhesion molecule-1 (VCAM-1) expression was significantly lower in C57BL/6-Kit(W-sh/W-sh) than in wild-type recipients; however, acute rejection scores, graft survival, inflammatory cells, or cytokine expression did not differ significantly. In the chronic rejection model, the number of mast cells/mm(2) of allograft tissue was significantly increased 52 days after transplantation in allografts transplanted into C57BL/6-Kit(+/+) but not C57BL/6-Kit(W-sh/W-sh) mice; however, no substantial differences were noted in graft coronary artery disease, graft inflammatory cells, or levels of graft tissue expression of cytokines or adhesion molecules. Cardiac allografts undergoing chronic rejection in wild-type C57BL/6-Kit(+/+) mice exhibit increased numbers of mast cells, but acute or chronic cardiac allograft rejection can develop in C57BL/6-Kit(W-sh/W-sh) mice even though these recipients virtually lack mast cells. These findings indicate that recipient mast cells are not required for acute or chronic cardiac allograft rejection in the models examined.

Systemic sclerosis as a model of chronic rejection in facial composite tissue transplantation

Chronic rejection remains a potential significant long-term problem of facial allograft transplantation. Scleroderma parallels chronic rejection in terms of its immunological pathophysiology and its histopathological processes. Through the analysis of facial changes in scleroderma we demonstrate how chronic facial allograft rejection may present and progress. 129 consecutive patients with a clinical diagnosis of scleroderma were recruited into the study. Static facial disease assessment was carried out through the analysis of digital photographs. Facial motion dysfunction was assessed using a modified House-Brackmann Grading Scale and an established maximal static response assay. Psychological evaluation comprised the Derriford Appearance Scale short-form (DAS), the Noticeability and Worry score and the Hospital Anxiety and Depression Scale (HADS). Static disease severity as measured using an observer-rated disfigurement scale revealed all grades of disease in the scleroderma cohort - from mild through to severe. Significant positive correlations were seen between observer rated disfigurement and DAS24, Noticeability and Worry scores. No significant relationship could be seen between the indices of facial motion impairment and psychological scores. Progressive facial deterioration seen over time in scleroderma provides a comprehensive spectrum of static and dynamic facial changes which may be encountered in chronic facial graft rejection. This study provides valuable insight into the potentially significant long-term sequelae of allogenic reconstructive transplantation.

Inhibition of tertiary lymphoid organs in a murine chronic rejection model

Inhibition of tertiary lymphoid organs in a murine chronic rejection model

Liver Transplantation in the Rat: Single-Center Experience With Technique, Long-term Survival, and Functional and Histologic Findings

Orthotopic liver transplantation (OLT) in rats is frequently used as an experimental model. Numerous surgical techniques have been developed that enable the investigator to conduct clinically relevant studies. The objective of this study was to develop a rat model of acute and chronic rejection, to explicitly study technical modifications of vascular anastomoses with precision, and to examine histopathologic and functional changes in the graft. With DA-(RT1av1) rats as donors and Lewis-(RT1) rats as recipients, arterialized OLT was performed using a combined suture, cuff, and splint method. Recipients were divided into 5 groups: syngeneic control rats (group 1), allogeneic control rats (group 2), allogeneic OLT rats with low-dose tacrolimus (FK506) immunosuppression (group 3), allogeneic OLT rats with high-dose tacrolimus immunosuppression (group 4), and allogeneic OLT rats with high-dose tacrolimus immunosuppression and retrograde reperfusion via the infrahepatic caval vein (group 5). After OLT, serum parameters were determined and hepatic biopsy specimens were sampled. We examined the effects of acute rejection with or without immunosuppression therapy at histopathologic evaluation. Liver grafts in syngeneic and allogeneic rats (groups 1, 2, 4, and 5) demonstrated normal serum parameters and histopathologic findings at 10 days after OLT, and 93% survival at 3 months. The simplified technique using 1 suture and 2 cuff anastomoses provided the best short- and long-term survival after OLT in all groups. Retrograde perfusion via the infrahepatic caval vein resulted in lower postoperative liver enzyme values. The present model is feasible, enabling comprehensive preclinical experimental research on liver transplantation. Furthermore, we provide helpful instructions for learning this surgical technique.

Increased Connective Tissue Growth Factor Expression in a Rat Model of Chronic Heart Allograft Rejection

Chronic rejection limits the long-term success of cardiac transplantation and the underlying cause of the disease is unknown. Connective tissue growth factor (CTGF) is considered as a mitogenic and chemotactic factor for fibroblasts, and is associated with cell proliferation and collagen synthesis. We evaluated the expression of CTGF in a rat model of heart allograft chronic rejection. Intra-abdominal heterotopic heart transplantation was performed from 20 Wistar rats to 20 Sprague-Dawley (SD) rats that received cyclosporine, mycophenolate mofetil and methylprednisolone as immunosuppression. Ten heart allografts were explanted at 2 and 8 weeks postoperatively for analysis of morphologic changes. The hearts from 10 normal Wistar rats served as a control group. Coronary artery density, luminal loss of myocardial coronary arteries, and myocardial fibrosis were measured. The expression of CTGF was studied by immunohistochemistry. Correlation between CTGF expression and development of cardiac allograft vasculopathy (CAV) or fibrosis was studied. Allografts harvested at 8 weeks postoperatively showed more coronary intimal proliferation, fibrosis and CTGF expression compared with the 2-week allografts (p < 0.05) and the controls (p < 0.01), but the coronary artery density was lower than in the control group (p < 0.05). However, the control group showed negligible CTGF expression. There were strong negative correlations between the gray value of CTGF protein expression and cardiac fibrosis and coronary intimal occlusion (r = -0.734, -0.713; p < 0.01), which demonstrated that CTGF protein expression was positively correlated with cardiac fibrosis and coronary intimal occlusion. CTGF is expressed in cardiomyocytes in CAV. Increased expression of CTGF in cardiac allografts is associated with development of CAV and fibrosis formation.

A new carotid artery transplantation model of rats

To establish a murine carotid artery transplantation model for the study of the chronic rejection, 80 rats were divided into two groups, an allotransplant (ACI-Lewis) group and an isotransplant (Lewis-Lewis) group (control group). The donor carotid artery and the recipient carotid artery were anastomosed by using a polyethylene cuff (internal diameter: 0.7 mm, length: 3 mm).The pathological changes of carotid artery transplant were observed 14, 28 and 56 days after the transplantation. The results showed that the model was successfully established in 95% of the animals. The chronic rejection-associated arteriosclerosis was induced 28 days after the transplantation. The new chronic rejection model of carotid artery by using cuff technique caused fewer traumas and was easy to make. The pathological changes of the transplant mimicked the chronic rejection-associated arteriosclerosis found in human transplant.

132: The Role of Mast Cells in Acute and Chronic Cardiac Allograft Rejection

The role of mast cells in transplant rejection remains controversial. Investigators have reported that mast cells promote the development of both acute and chronic rejection. In contrast, mast cells have also been shown to play an immunosuppressive/protective role in skin transplant models. To better define the role of mast cells in cardiac rejection, both acute and chronic rejection models were performed utilizing mast cell-deficient mice.

Bacteriocins From Lactic Acid Bacteria Increases Tumor Necrosis Factor-α Expression in a Rat Kidney Model of Chronic Rejection

Chronic allograft dysfunction is the primary cause of graft loss after the first posttransplantation year. Bacteriocins are biologically active proteins exhibiting antimicrobial properties against other bacterial species, which are usually closely related to the producer organism. The objective of our study was to determine whether lactic acid bacterial bacteriocins were associated with tumor necrosis factor (TNF)-α observed in a rat kidney model of chronic rejection. Using a kidney model of chronic rejection in the rat, we administered cyclosporine (CsA) immunosuppression (5 mg/kg/d). One group of animals was treated with bacteriocins, and the other was left untreated. Grafts were harvested after transplantation for standard histological studies. The expression of TNF-α was demonstrated using immunohistochemistry of frozen sections of the grafts. We observed a greater increase in the expression of TNF-α among the group treated with bacteriocins compared with the untreated group. These results showed that lactic acid bacterial bacteriocins were associated with TNF-α in our kidney graft model.