摘要:

Programmed cell death (PCD) is currently one of the most intensively studied areas in cell biology. Substantial evidence now exists demonstrating the integral role of PCD in many fundamental immunologic processes; therefore, understanding the mechanisms of PCD may provide advances with broad implications in immunobiology. This Overview provides a definition of PCD, a description of known PCD biochemical pathways, and finally a discussion of the implications of PCD in transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Chronic allograft rejection remains a major barrier to successful long-term allograft transplantation in humans. Chronic allograft rejection is characterized by the appearance of arterial lesions with concentric intimal thickening. This study investigates the development and control of chronic rejection in hamster cardiac xenografts transplanted into Lewis rats.Methods.Chronic rejection in the xenograft model involves transplantation of hamster hearts into Lewis rats treated with leflunomide (Lef) continuously at 15 mg/kg/day. The allograft model involves transplantation of Lewis hearts into Fisher-334 rats treated with cyclosporine (CsA) at 2.5 mg/kg for 5 days.Results.The average scores of arterial intimal thickening on day 45 after transplantation were 1.89±0.43 in the xenograft and 2.50±0.72 in the allograft. The basic pathology of both xenografts and allografts undergoing chronic rejection was arterial intimal thickening comprising smooth muscle cell proliferation, mononuclear cell infiltration, and fibrosis. The majority of cells infiltrating the arterial intima and myocardium were T cells and macrophages. Compared with the allograft, intimal edema, matrix deposition and fibrinoid necrosis were specifically presented in the xenografts and generally involved the larger arteries. The predominant isotype of antibody deposited was IgM in xenografts and IgG in allografts. When combined Lef and CsA therapy was initiated on day 45 after transplantation, the changes of chronic rejection were reversed in both xenografts and allografts by day 90. The scores of intimal thickening were significantly reduced to 0.97±0.45 and 1.48±0.56, respectively.Conclusions.We conclude that chronic rejection can be induced in xenografts under conditions of inadequate immunosuppression. Chronic rejection in xenografts involves arterial lesions that bear some histological similarities to, as well as differences from, those observed in chronically rejected allografts. Finally, combination therapy with CsA and Lef reduced the incidence and severity of the intimal lesions in both chronically rejecting xenografts and allografts.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.We designed an antisense phosphorotioate oligodeoxynucleotide (oligo) to specifically inhibit the expression of rat intercellular adhesion molecule-1 (ICAM-1) mRNA (IP-9125).Methods.IP-9125 oligo was delivered intravenously by osmotic pump alone or in combination with cyclosporine (CsA) to recipients in order to prevent the rejection of kidney or heart allografts. In additional experiments, kidney allografts were perfused with IP-9125 before grafting.Results.IP-9125 inhibited ICAM-1 mRNA and ICAM-1 protein expression in rat aortic endothelial cells; scrambled controls IP-12140 and IP-13944 were ineffective. Untreated ACI (RT1a) recipients rejected Lewis (RT11) kidney allografts at a mean survival time of 8.5±1.1 days. A 14-day intravenous administration of 2.5 mg/kg/day IP-9125 prolonged the survival of kidney allografts to 39.2±16.4 days; 5.0 mg/kg/day, to 43.0±17.5 days; and 10.0 mg/kg/day, to 50.4±21.6 days. In contrast, a scrambled control IP-12140 was not effective. A combination of 10 mg/kg/day IP-9125 and 1.0 mg/kg/day CsA delivered for 14 days synergistically extended kidney allograft survival times 88.5±7.5 days. In contrast, the combination of 10.0 mg/kg/day control IP-12140 with CsA was ineffective (20.7±3.2 days) when compared with CsA alone (20.2±4.0 days). Similar results were obtained for heart transplants in recipients treated with IP-9125 alone or in combination with CsA. Furthermore, in situ immunostaining showed that IP-9125 significantly reduced the expression of ICAM-1 protein in kidney allografts. Finally, perfusion of kidney grafts alone with 20.0 mg per 2 ml of IP-9125 protected kidney allografts from rejection (37.5±7.5 days;P<0.001), whereas perfusion with 20 mg per 2 ml of control IP-12140 was ineffective (12.6±5.0 days).Conclusions.Rat ICAM-1 IP-9125 oligo inhibits ICAM-1 protein expression in vitro and in vivo as well as blocks allograft rejection when used for pretreatment of donors, graft perfusion, or postoperative treatment of recipients.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Tissue factor (TF) is a membranous protein normally present on the surface of the fibroblasts and smooth muscle cells of vessels. TF is an initiation factor for blood coagulation, and its expression is induced on macrophages and endothelial cells during the inflammatory or immune response. We studied the significance of TF expression in warm ischemic-reperfusion injury of the liver using a rat model.Methods.Following laparotomy of Lewis rats, the branches of the hepatic artery and portal vein leading to the median, left, and caudate lobes of the liver were clamped for 2 hr. The liver was reperfused after 120 min of ischemia. Rats were killed at 0, 1, 3, 5, 8, and 12 hr after reperfusion, and liver tissues were harvested. TF activity was measured by the chromophilic substrate S-2222. TF expression was studied by immunohistochemical staining with the monoclonal antibody HTF-K108.Results.TF activity in the blood showed a peak at 3 hr after reperfusion (8.9±0.5 U/L), then decreased and returned to the normal level by 12 hr (0.9±0.3 U/L). TF activity in ischemic liver tissue increased gradually over 12 hr after reperfusion (1223±275 U/g dry weight before ischemia and 2545±284 U/g weight at 12 hr after reperfusion). Histologically spotty necroses were observed in the liver tissue 5 hr after reperfusion. The necrotic area extended and encompassed almost all of the ischemic liver by 12 hr after reperfusion. Histochemically, TF staining was negative on the hepatocytes and slightly positive on sinusoid cells of the normal liver. On the other hand, TF was strongly stained, especially on the hypertrophic monocytic cells accumulating at the site of the necrosis, but staining was not evident on the necrotic hepatocytes. A slight degree of TF staining was observed on the alveolar epithelium of the lung, irrespective of liver ischemia and reperfusion.Conclusion.These results demonstrate that TF plays an important role in the development of the hepatic ischemic-reperfusion injury, and the subsequent microcirculatory incompetence might cause the formation of microthrombus and the development of necrosis.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Recent observations provide evidence the complement is involved in the pathophysiology of ischemia/reperfusion injury. In this study, we assessed the impact of complement inhibition on hepatic micro-circulation and graft function using a rat model of liver transplantation.Methods.Arterialized orthotopic liver transplantation was performed in Lewis rats after cold preservation (University of Wisconsin solution, 4°C, 24 h). Eight animals received the physiological complement regulator soluble complement receptor type 1 (sCR1) intravenously 1 min before reperfusion. Controls received Ringer's solution (n=8). Microvascular perfusion, leukocyte adhesion, and Kupffer cell phagocytic activity were studied 30-100 min after reperfusion by in vivo microscopy.Results.Microvascular perfusion in hepatic sinusoids was improved in the sCR1 group (87±0.7% vs. 50±1%;P<0.001). The number of adherent leukocytes was reduced in sinusoids (68.3±4.7 vs. 334.1±15.8 [adherent leukocytes per mm ≤ liver surface];P<0.001) and in postsinusoidal venules after sCR1 treatment (306.6±21.8 vs. 931.6±55.9 [adherent leukocytes per mm ≤ endothelial surface];P<0.001). Kupffer cell phagocytic activity was decreased in the sCR1 group compared to controls. Postischemic bile production reflecting hepatocellular function was increased by almost 200% (P=0.004) after complement inhibition. Plasmatic liver enzyme activity was decreased significantly upon sCR1 treatment, indicating reduced parenchymal cell injury.Conclusions.Our results provide further evidence that the complement system plays a decisive role in hepatic ischemia/reperfusion injury. We conclude that complement inhibition by sCR1 represents an effective treatment to prevent reperfusion injury in liver transplantation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Lung dysfunction after transplantation continues to be a significant clinical problem. Soluble complement receptor 1 (sCR1) is a potent inhibitor of complement activation. We evaluated the inhibitory effect of sCR1 on complement activation and reperfusion injury in pig lung allografts.Methods.In a randomized and blinded study, left lung transplantation was performed in 13 pigs. Donor lungs were flushed and then stored for 30 hr at 4°C. Control pigs (n=7) received saline, and the treatment group (n=6) received 15 mg/kg sCR1 1 hr before reperfusion. One hour after reperfusion, the right pulmonary artery was clamped for 10 min to assess the function of the transplanted lung. Pulmonary function was assessed again on day 3.Results.Complement inhibition was 93% in the sCR1 group and returned to baseline (8% inhibition) after 3 days. There was a trend toward a higher partial pressure of oxygen at 1 hr in the sCR1 group compared with the control group (mean ± SE: 408±42 mmHg vs. 288±69 mmHg,P=0.19). Alveolar ventilation was better in the sCR1 group than in the control group (P=0.01) at 1 hr. Mixed venous saturation was significantly lower in the control group at both 1 hr (P=0.02) and 3 days (P=0.001). The wet/dry weight of the lung tissue was lower in the sCR1 group compared with the control group on day 3 (P<0.05). Chemiluminescence, an index of phagocyte priming, was lower in the sCR1 group when cells were stimulated with complement opsonized zymosan but not when stimulated with zymosan or phorbol myristate acetate.Conclusion.sCR1 improves ventilation, reduces pulmonary edema, and may be beneficial in improving posttransplant lung oxygenation.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Lamivudine is a potent inhibitor of hepatitis B virus replication. Little has been reported about the efficacy and safety of lamivudine in the treatment of chronic hepatitis B in the setting of renal transplantation.Methods.Two patients were treated for chronic hepatitis B with lamivudine and subsequently underwent renal transplantation. Four other patients were treated with lamivudine for reactivation of hepatitis B after renal transplantation. Chronic hepatitis B was proven histologically in all the patients. The doses of lamivudine ranged from 100 to 150 mg/day. Hepatic enzyme and viral markers were monitored.Results.Lamivudine was well tolerated for a median duration of 8 months (range, 4-14 months) without significant side effects. Viral replication was suppressed, as evidenced by negative conversion of serum hepatitis B virus DNA in all the patients. Hepatic enzyme was also normalized. Modification of doses of immunosuppressant regimen was not required in using lamivudine in all patients. One patient experienced acute rejection and responded to solumedrol pulse therapy with normalization of graft function. Normal graft function was maintained in other patients while they were treated with lamivudine.Conclusion.Lamivudine was a safe and effective therapy for activated hepatitis B in renal transplant recipients in the short term.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.Hepatic graft reperfusion is associated with inflammatory processes of unknown relevance to the fate of graft. This study aimed to clarify this relevance by histochemical analyses of human hepatic grafts.Methods.Paired tissue samples were taken at the end of cold preservation and 2 hr after reperfusion (n=39). From six additional grafts, biopsies were performed at the end of cold preservation only. Injury or inflammatory markers of sinusoidal endothelium (von Willebrand factor-related antigen [vWF]), Kupffer cells (25F9), platelets (CD62), neutrophil leukocytes (CD11b), interleukin (IL)-1β, intercellular adhesion molecule (ICAM)-1, and HLA-DR were evaluated semi-quantitatively by indirect immunoperoxidase staining. Steatosis was also evaluated by hematoxylin and eosin staining.Results.vWF, CD62+platelet aggregation, CD11b+leukocytes, and IL-1β levels increased after reperfusion, and these levels correlated with prereperfusion levels. Not only vWF, CD62+platelets, CD11b+leukocytes, IL-1β, ICAM-1, and steatosis after reperfusion, but also IL-1β, ICAM-1, and steatosis before reperfusion correlated with postoperative peak transaminase. Furthermore, vWF, CD11b+leukocytes, 25F9+macrophages, and ICAM-1 after reperfusion were associated with primary graft nonfunction and strong expressions of ICAM-1 or HLA-DR with early acute rejection. Although some markers (IL-1β, CD62+platelets, and CD11b+leukocytes) correlated with preharvesting parameters (donor age or length of intensive care unit stay), none showed any significant correlation with cold preservation.Conclusion.Synergistic inflammatory events in the hepatic graft at reperfusion, which have a significant impact on the later clinical course, are largely defined and precipitated by injury or activation of nonparenchymal cells preceding reperfusion or even graft harvesting.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.The key role of anti-galactoseα1,3-galactose (anti-αGal) xenoantibodies in initiating hyperacute xenograft rejection has been clearly demonstrated using a variety of in vitro and in vivo approaches. However, the role of anti-αGal antibodies in mediating post-hyperacute rejection mechanisms, such as antibody-dependent cellular cytoxicity, remains to be determined, primarily because of the lack of a small animal model with which to study this phenomena.Methods.Hearts from wild-type mice were transplanted heterotopically into α1,3-galactosyltransferase knockout (Gal KO) mice, which like humans develop antibodies to the disaccharide galactoseα1,3-galactose (Gal). At the time of rejection, hearts were examined histologically to determine the mechanism of rejection.Results.Hearts from wild-type mice transplanted into high-titer anti-αGal recipients were rejected in 8-13 days. Histological examination demonstrated a cellular infiltrate consisting of macrophages (80-90%), natural killer cells (5-10%), and T cells (1-5%). In contrast, wild-type hearts transplanted into low anti-Gal titer recipients demonstrated prolonged (>90 day) survival. However, a significant proportion (30-40%) of these underwent a minor rejection episode between 10 and 13 days, but then recovered ("accommodated").Conclusions.The results of this study suggest that the Gal KO mouse is a useful small animal vascularized allograft model, in which the role of anti-αGal antibody in graft rejection can be studied in isolation from other rejection mechanisms. The titer of anti-αGal antibody was found to be the critical determinant of rejection. The histopathological features of rejection in this model are very similar to other models of delayed xenograft rejection, in both the timing and composition of the cellular infiltrate. The Gal KO mouse therefore provides a new rodent model, which will aid in the identification of the distinct components involved in the pathogenesis of delayed xenograft rejection.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background.In pig-to-primate/human xenografts, hyperacute rejection of primarily vascularized organs usually occurs in 10-60 min and is due to the reaction of the recipients' natural antibodies with antigens expressed on the donor endothelium, the fixation of complement, and ultimately vascular stasis and hemorrhage. Surprisingly, the major target of the natural antibodies is the disaccharide galactose-α(1,3)galactose (Galα(1,3)Gal), which is found on many different molecules in pig tissues and reacts with naturally occurring human anti-pig IgM and IgG antibodies. There are a number of strategies to remove/block/alter Galα(1,3)Gal expression in pig tissues, all of which involve the expression of transgenes in pigs. To overcome the difficulty of preclinical studies using primates, we describe a model of hyperacute rejection of heart transplants to Gal o/o mice, which are similar to humans in that they have anti-Galα(1,3)Gal antibodies.Methods.Gal o/o mice received skin or heart grafts from Gal+mice or rats, and additional antibody and complement were provided; hyperacute rejection was monitored by observation and histology.Results.Galα(1,3)Gal+mouse tissues (skin or heart) are not rejected by Gal o/o mice. This was not unexpected, as mice do not utilize alloantibody/complement systems satisfactorily in experimental transplantation studies. However, with the addition of anti-Galα(1,3)Gal antibody and complement, hyperacute rejection of hearts can occur in 10-20 min; it is mediated by IgM, not IgG, antibodies and leads predominantly to tissue hemorrhage.Conclusion.Galα(1,3)Gal antigen modification by expression of the H transferase cDNA leads to "indefinite" survival (>120 min) and no hyperacute rejection, which shows that this model is suitable for the study of antibody-mediated rejection of relevance to pig-to-human xenografts.

ISSN:0041-1337    

出版商:OVID    

年代:1998

数据来源: OVID