Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis.

Akyurek, LM; Johnsson, Cecilia; Lange, David; Georgii-Hemming, Patrik; Larsson, Erik; Fellström, Bengt; Funa, Keiko; Tufveson, Gunnar

doi:10.1172/jci1177

Cited by 52 publications

(25 citation statements)

References 44 publications

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“…at an original magnification of ϫ100 using a conventional light microscope. A digitized image of each section was captured, and the areas within the lumen and the internal and external elastic lamina were circumscribed manually and measured as previously described (25). From these measurements, a quotient for the thickness of the intima (Q int ) was calculated.…”

Section: Histology and Analysis Of Aortic Graftsmentioning

confidence: 99%

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Ensminger

Spriewald

Sorensen

et al. 2001

The Journal of Immunology

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Blockade of the CD40-CD154 pathway can inhibit CD4+ T cell activation but is unable to prevent immune responses mediated by CD8+ T cells. However, even in the absence of CD8+ T cells, inhibition of the CD40-CD154 pathway is insufficient to prevent the development of transplant arteriosclerosis. This study investigated the mechanisms of transplant arteriosclerosis in the absence of the CD40 pathway. C57BL/6 CD40−/− (H2b) recipients were transplanted with MHC-mismatched BALB/c (H2d) aortas. Transplant arteriosclerosis was evident in both CD40−/− and CD40+/− mice (intimal proliferation was 59 ± 5% for CD40−/− mice vs 58 ± 4% for CD40+/− mice) in the presence or absence of CD8+ T cells (intimal proliferation was 46 ± 7% for CD40−/− anti-CD8-treated mice vs 50 ± 10% for CD40+/− anti-CD8-treated mice), confirming that CD8+ T cells are not essential effector cells for the development of this disease. In CD40−/− recipients depleted of CD8+ T cells, the number of eosinophils infiltrating the graft was markedly increased (109 ± 24 eosinophils/grid for CD40−/− anti-CD8-treated mice vs 28 ± 7 for CD40+/− anti-CD8-treated mice). The increased presence of eosinophils correlated with augmented intragraft production of IL-4. To test the hypothesis that IL-4 was responsible for the intimal proliferation, CD8 T cell-depleted CD40−/− recipients were treated with anti-IL-4 mAb. This resulted in significantly reduced eosinophil infiltration into the graft (12 ± 5 eosinophils/grid for CD40−/− anti-CD8+, anti-IL-4-treated mice vs 109 ± 24 for CD40−/− anti-CD8-treated mice), intragraft eotaxin, CCR3 mRNA production, and the level of intimal proliferation (18 ± 5% for CD40−/− anti-CD8+-, anti-IL-4-treated mice vs 46 ± 7% for CD40−/− anti-CD8-treated mice). In conclusion, elevated intragraft IL-4 production results in an eosinophil infiltrate and is an important mechanism for CD8+ T cell-independent transplant arteriosclerosis in the absence of CD40-CD154 costimulation.

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Section: Histology and Analysis Of Aortic Graftsmentioning

confidence: 99%

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Ensminger

Spriewald

Sorensen

et al. 2001

The Journal of Immunology

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“…It is di¤cult to dissect, however, the alloantigenspeci¢c from non-speci¢c e¡ects of this therapy in such a model. In a rat model of tolerance, however, protection against CR is not abrogated by prolonged ischaemia in a second challenge graft, suggesting tolerance is su¤cient to protect from non-immunological injury (Akyurek et al 1998). …”

Section: (Iii) Ischaemia and Reperfusionmentioning

confidence: 99%

Tolerance and chronic rejection

Womer

Lee

Madsen

et al. 2001

Phil. Trans. R. Soc. Lond. B

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The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity called chronic rejection (CR). Recent reports suggest an improvement in long-term renal allograft survival, although it is not clear from these data whether a true reduction of biopsy-proven CR has occurred. Although newer immunosuppressive medications have greatly reduced the incidence of acute rejection (AR) in the early post-transplantation period, the ideal therapy for both AR and CR would be to achieve a state of tolerance. By de¢nition, such a state should allow for inde¢nite allograft survival, with no histopathological evidence of CR, despite immunocompetence in the host (i.e. without the need for chronic immunosuppression). Although several experimental studies are able to achieve tolerance, with clear improvement in allograft survival, detailed studies on graft function and morphology are often not included. This review will discuss possible ways that tolerance induction could lead to a CR-free state. General mechanisms of CR and transplantation tolerance induction are discussed as well as the di¤culties in translating small animals studies into large animals and humans.

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“…1,3,4 Increased apoptosis, including vascular EC and smooth muscle cell (SMC), has been observed in acute and chronic rejection; such apoptosis probably is mediated through the Fas/Fas-Ligand (Fas-L) pathway. [5][6][7][8] Fas-Lϩ T cells and macrophages bind to Fasϩ vascular cells, inducing apoptosis. One of earliest features of CAV is the adherence of monocytes to the endothelium, followed by their migration into the intima, which may enhance the development of atherosclerotic lesions.…”

mentioning

confidence: 99%

Overexpression of Soluble Fas Attenuates Transplant Arteriosclerosis in Rat Aortic Allografts

et al. 2002

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Background-The killing of vascular cells by activated macrophages is an important step in the process of destabilization of the arterial wall. The death receptor Fas is implicated in vascular cell death. Hence, we extended our studies in a rat aortic allograft model, using adenovirus-mediated overexpression of soluble Fas (sFas) to block Fas binding to Fas ligand (Fas-L). The contribution of Fas to vascular cell injury and consequent transplant arteriosclerosis was investigated. Methods and Results-Activated monocytes in the presence of macrophage colony-stimulating factor induce endothelial cell apoptosis in vitro, which was significantly inhibited by adenovirus-mediated sFas overexpression. Next, donor rat abdominal aortas were either untreated or transduced with adenoviruses encoding (1) rat soluble Fas (Ad3rsFas), (2) no insert (Ad3Null), and (3) ␤-galactosidase (Ad3nBg). A total of 175 aortic grafts were harvested 2 to 90 days after transplantation. Vascular cell apoptosis and CD45ϩ cell infiltration were significantly reduced in Ad3rsFas-transduced aortas, as compared with control allografts. Moreover, the control allografts developed marked intimal thickening, whereas Ad3rsFas-transduced allografts had significantly less neointima until the 90-day time point. Key Words: arteriosclerosis Ⅲ apoptosis Ⅲ endothelium Ⅲ inflammation Ⅲ gene therapy C ardiac allograft vasculopathy (CAV), characterized by the development of transplant arteriosclerosis, remains the leading cause of late graft failure and patient death in heart transplantation. The archetypal pathological findings of CAV are diffuse concentric intimal proliferation and intense mononuclear cell infiltration, including T cells and macrophages, in most graft vessels. 1,2 Although the precise molecular and cellular mechanisms are not yet elucidated, endothelial cell (EC) injury and recipient inflammatory response are believed to be crucial in the development of CAV. 1,3,4 Increased apoptosis, including vascular EC and smooth muscle cell (SMC), has been observed in acute and chronic rejection; such apoptosis probably is mediated through the Fas/Fas-Ligand (Fas-L) pathway. 5-8 Fas-Lϩ T cells and macrophages bind to Fasϩ vascular cells, inducing apoptosis. One of earliest features of CAV is the adherence of monocytes to the endothelium, followed by their migration into the intima, which may enhance the development of atherosclerotic lesions. 9 Numerous investigations have focused on the molecular mechanism of monocyte attraction and migration into vascular tissues; little attention, however, has been paid to the actual role of infiltrating macrophages in the mediation of CAV. Conclusions-sFasMacrophage colony-stimulating factor (MCSF), which is elevated within inflammatory atherosclerotic lesions, 9 was shown to block spontaneous monocyte apoptosis and to stimulate monocyte differentiation, proliferation, and activation. 10 We have previously reported that monocytes, in the presence of MCSF, switched to a phenotype capable of inducing SMC apoptosis. 11 In ...

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Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis.

Cited by 52 publications

References 44 publications

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Critical Role for IL-4 in the Development of Transplant Arteriosclerosis in the Absence of CD40-CD154 Costimulation

Tolerance and chronic rejection

Overexpression of Soluble Fas Attenuates Transplant Arteriosclerosis in Rat Aortic Allografts

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