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A Mennander

Publications and source records attributed to A Mennander.

33 records · Page 2Linked to original sources
PubMed1992

Will chronic rejection ever respond to treatment?

In acute allograft rejection, the end-point is irreversible damage of the graft (microvascular) endothelium by inflammatory cells and antibodies, and thrombosis and necrosis of the graft. In chronic rejection a prime manifestation, common to all transplants, is persistant perivascular inflammation and concentric longitudinal allograft arteriosclerosis affecting particularly the first and second order intragraft branches of transplant arteries (Table 1). Thus, to understand the molecular mechanism of chronic rejection, we should know how the immune inflammation regulates vascular smooth muscle cell (SMC) proliferation.

Animals↗
PubMed1992

Chronic rejection of rat aortic allografts: effect of inhibition of the thromboxane cascade.

Non-immunosuppressed rat aortic allografts from DA (RT1av1) to WF (RT1u) strain develop, after a short reversible acute rejection episode, chronic arteriosclerotic changes in the vascular wall, which are indistinguishable from those seen in human allografts during chronic rejection. Incubation of the aortic wall segments in vitro and immunochemical assays demonstrated that the allografts synthesized increased amounts of TxB2, but not 6-keto-PGF1alpha, or LTB4, compared to syngenic or normal aortas. The two major cellular components of the vascular wall, intima and adventitia, were incubated separately after microdissection. TxB2 was produced in the adventitia, whereas most of the 6-keto-PGF1alpha was synthesized in the intima. Administration of a specific TxA2 receptor inhibitor to the recipient rat reduced significantly the proliferation of adventitial inflammatory cells and the intimal smooth muscle cells. Nevertheless, it only delayed but did not inhibit the overall sclerosis of the intima.

Animals↗
PubMed1992

Towards understanding the pathophysiology of chronic rejection.

Chronic allograft rejection is the major reason why allografts are lost. While only 2%-3% of all allografts are lost during the first year to irreversible acute rejection, approximately 6%-7% are lost during each subsequent year to chronic rejection. The major manifestation of chronic rejection in all organs is persistent perivascular inflammation and allograft arteriosclerosis. Bearing this in mind, we have developed a model to investigate the pathophysiology of allograft arteriosclerosis using aortic transplantations between inbred rat strains. The results obtained thus far indicate that several different inflammatory cascades are operative within the vascular wall during allograft arteriosclerosis. The relative importance of these different cascades, and particularly the role of growth factors as final effectors, has not yet been defined. Attempts to suppress allograft arteriosclerosis under experimental conditions have already met with some success: under conditions where no immunosuppression is provided we have been able to delay the process by at least 3 months, though we have not been able to block it indefinitely. It may be expected, however, that once the inflammatory cascades leading to smooth muscle cell replication in the allograft media and their influx into the intima are better defined, more specific approaches to the inhibition of allograft arteriosclerosis will be developed.

Animals↗
PubMed1992

Chronic rejection of rat aortic allografts. III. Synthesis of major eicosanoids by vascular wall components and effect of inhibition of the thromboxane cascade.

We have previously demonstrated that rat aortic allografts from the DA (RT1a) to the WF (RT1v) strain develop chronic arteriosclerotic changes in the vascular wall after a short spontaneously reversible acute rejection episode. These changes, which are lacking in syngeneic DA-to-DA control grafts, are virtually identical with those observed in human allografts during chronic rejection. In this study we have investigated whether eicosanoids are involved in the generation of arteriosclerotic changes. Incubation of aortic wall rings in vitro and immunochemical assays demonstrated that the arteriosclerotic allografts synthesize significantly more thromboxane B2 (TxB2) but not 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) or leukotriene B4. The increased synthesis of TxB2 in the allografts persisted for at least 5 months after transplantation. Separate incubation of the two major components of the vascular wall, after microdissection of the intima and (media plus) adventitia, demonstrated that most of the synthesis of TxB2 during chronic rejection was due to the outer layer of aorta, presumably the inflammatory cells of the adventitia. In contrast, most of the 6-keto-PGF1 alpha was synthesized by the inner layer of the aorta, presumably the endothelial cells and the smooth muscle cells of the intima. Administration of 1 mg.kg-1 x day-1 of a specific TxA2 receptor inhibitor, GR32191B, to the recipient rat reduced the proliferative response of inflammatory cells in the adventitia by 30%, as detected by in vivo tritiated-thymidine (3H-TdR) labeling and autoradiography, but did not reduce the proliferative response of smooth muscle cells in the media and intima.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chronic rejection of rat renal allograft. I. Histological differentiation between chronic rejection and cyclosporin nephrotoxicity.

Chronic allograft rejection is both a clinical and a histopathological diagnosis. Until recently, the histological definition of chronic renal allograft rejection was based on clinical diagnostic biopsies, where the evidence was partially obscured by recurrence of the original renal disease, and/or by administration of immunosuppressive drugs. In this communication, we present an experimental rat model for chronic renal allograft rejection, devoid of recurrence of the original disease. By comparing allografts to similarly immunosuppressed syngeneic transplants, we define which histological features should be attributed to chronic rejection and which to cyclosporin nephrotoxicity. Rat renal transplants were performed from DA (Ag-B4, RT1av1) to WF strain (Ag-B2, RT1u) or, for control, to DA strain, and immunosuppressed for 2 or 3 weeks with cyclosporin using a variety of different dosages. The animals were monitored weekly for serum creatinine levels and for blood cyclosporin concentrations, and core needle biopsies were performed on the grafts at regular intervals. At 3 months post-transplantation the animals were sacrificed and a complete histopathological evaluation was performed. Thirty-one histological variables were scored blindly by two investigators and separately for the graft interstitium, glomeruli, tubuli, and the graft vasculature. The following histological alterations were significantly more prominent in allografts than in similarly immunosuppressed syngeneic transplants: the intensity of interstitial inflammation, particularly the degree of pyroninophilia within the inflammatory cell population; the extent of glomerular mesangial matrix increase, basement membrane thickening, and glomerular sclerosis; the increase in the vascular intimal thickness affecting in particular the first and second order branches of the renal artery; and the obliteration of the graft vasculature. These alterations were considered as being primarily due to chronic rejection. In contrast, the extent of interstitial fibrosis and the extent of tubular changes, including tubular epithelial vacuolation, epithelial atrophy, and tubular basement membrane changes, were not significantly different in the allografts as compared to the syngeneic controls. These alterations were attributed primarily to cyclosporin nephrotoxicity. Serial monitoring of the grafts by needle biopsies clarified the sequence of events in the development of the chronic alterations in the transplant. The first event, as expected, was tubulointerstitial pyroninophilic inflammation, resembling that of acute episodes of rejection. This was significantly stronger and appeared earlier in allografts immunosuppressed for 2 rather than for 3 weeks. Vascular alterations developed next. The last to develop were the glomerular lesions.

Animals↗
PubMed1991

Chronic rejection of rat aortic allograft. II. Administration of cyclosporin induces accelerated allograft arteriosclerosis.

Rat aortic allografts immunosuppressed with cyclosporin--but not with azathioprine or steroids--develop an early inflammatory lesion in the subendothelial space. This "endothelialitis" is followed by an influx of proliferating smooth muscle cells into the intima, resulting in intimal thickening and accelerated arteriosclerosis. Administration of azathioprine and steroids largely ameliorates the development of the accelerated lesion. Similar endothelialitis and accelerated arteriosclerosis have been observed previously in the autopsy material of cardiac transplant recipients. Our results confirm the suggestion that the development of accelerated allograft arteriosclerosis is most likely linked to cyclosporin administration.

Animals↗
PubMed1990

Signal transduction during in vitro lymphocyte homing.

Lymphocyte binding to endothelium is a necessary prerequisite for lymphocyte homing through endothelium. This is mediated by the binding of ligands on endothelial cells to lymphocyte surface homing receptors. We show in this paper that the intracellular second messenger pathways involved in interferon gamma-induced intercellular adhesion molecule 1 upregulation on endothelial cells are protein kinase C and calcium dependent. Lymphocyte binding to endothelial cells is enhanced by both platelet activating factor and interleukin 1 alpha. Platelet activating factor added to endothelial cultures increases lymphocyte binding within 10 min and operates via protein kinase C but not via cAMP. On the other hand interleukin 1 alpha increases binding within 4 hr and operates via cAMP but not via protein kinase C. These results imply that different mediators of inflammation can activate different signal transduction pathways but lead to similar increases in lymphocyte binding.

Animals↗
PubMed1990

Activation of protein kinase C is crucial in the regulation of ICAM-1 expression on endothelial cells by interferon-gamma.

ICAM-1 (CD54) is expressed on endothelial cells and serves as an important ligand for the white cell adhesion molecule CD11a/CD18 (LFA-1). Many studies have demonstrated that increased numbers of white cells binding to endothelial cells correlate with the level of ICAM-1 expression on endothelial cells. Several cytokines, including IFN-gamma, increase ICAM-1 expression in cultured human endothelial cells. We have analysed the second intracellular messenger pathways involved in IFN-gamma-induced up-regulation of ICAM-1 expression in endothelial cells. IFN-gamma induced a rapid activation of phospholipase C, leading to a breakdown of phosphoinositoldiphosphate (PIP2) into diacyglycerol (DAG) and inositoltriphosphate (IP3). DAG is a natural activator of the protein kinase C pathway. We were able to show that the effect induced by IFN-gamma could be inhibited by a protein kinase C inhibitor, H7, in a dose-dependent manner and mimicked by PMA, which stimulates protein kinase C. IFN-gamma induced a 5-fold translocation (activation) of protein kinase C from the cytosol into the endothelial cell membrane. Elevation of the IP3 levels led to activation of the calcium-dependent pathway. An inhibitor of calcium calmodulin, W7, decreased the IFN-gamma induced ICAM-1 expression, and addition of calcium ionophore to endothelial cells could replace IFN-gamma in the up-regulation of ICAM-1. Finally, IFN-gamma caused a significant increase in the calcium flux of endothelial cells. cAMP and cGMP had no effect on the regulation of ICAM-1 expression on cultured human endothelial cells.

Calcium↗
PubMedDate not supplied

Chronic rejection in rat aortic allografts. An experimental model for transplant arteriosclerosis.

Chronic rejection has several histological appearances, depending on the type of organ graft. Common to all of them is transplant arteriosclerosis associated with an ongoing inflammatory response in the transplanted graft. To the contrary of classical atherosclerosis, in which the manifestations are mostly focal, proximal, and asymmetric, transplant arteriosclerosis is generalized, and the intimal thickening is concentric. In this article, we describe an experimental animal model whereby transplant arteriosclerosis may be investigated in the inbred rat. Aortic allografts were transplanted from DA (RTIa) to major histocompatibility complex-incompatible WF (RTIv) rats or, for control, to rats of the DA strain. Transplantation was followed by an acute inflammation episode in the aortic adventitia of the allograft, largely lacking in the syngeneic graft, with a prominence of lymphoid activation markers (Cd25) in the cells of the inflammatory infiltrate. The inflammation episode peaked at 2 months after transplantation, became attenuated, and was followed by a proliferative response of myocytes in the allograft media. An increase in the migration of myocytes to the subendothelial space (presumably through small breaks generated in the internal elastic lamina) was observed thereafter, and myocyte proliferation continued in the intima with some intermingled macrophages. Finally, necrosis and disappearance of myocytes and their replacement by fibrous tissue were observed in the media. These alterations are virtually identical with the vascular lesion of chronically rejecting parenchymal organ transplants in human subjects. We suggest that aortic allografts exchanged between histoincompatible rat strains may be used as an experimental model for transplant arteriosclerosis.

Animals↗
PubMedDate not supplied

Endothelialitis and accelerated arteriosclerosis in human heart transplant coronaries.

We have analyzed the autopsy material of 11 cardiac allograft recipients, whose grafts became nonfunctional less than 1 year after transplantation. All patients had received routine triple-drug immunosuppression. Two of these patients showed accelerated transplant arteriosclerosis; the graft loss was associated with strong intimal proliferative response affecting the first-order and second-order intramuscular branches of the major coronary vessels. Histologic evidence showed only a slight inflammatory reaction in the vascular adventitia. The media was mostly intact, and the internal elastic lamina showed occasional breaks. A very prominent inflammatory reaction was noted in the subendothelial space in the intima. Immunohistochemistry with monoclonal antibodies revealed that the luminal part of the intima was invaded by anti-leukocyte common antigen and anti-UCHL1 positive T lymphocytes, whereas the abluminal part consisted mostly of anti-smooth muscle alpha-actin-positive smooth muscle cells. We call this subendothelial accumulation of lymphocytes endothelialitis. The suggestion has been made that accelerated arteriosclerosis may be associated with cyclosporine treatment. Correlation with the recipient's cytomegalovirus status in this study suggests that cytomegalovirus infection may contribute to the development of endothelialitis and accelerated arteriosclerosis in heart transplant recipients.

Adult↗
PubMedDate not supplied

Chronic rejection in rat aortic allografts. IV. Effect of hypercholesterolemia in allograft arteriosclerosis.

Rat aortic allografts transplanted across histoincompatible strains develop arteriosclerotic alterations in the vascular wall that are virtually indistinguishable from those observed in human heart allografts during chronic rejection. In this study we have investigated whether hypercholesterolemia in the recipient rat accelerates allograft arteriosclerosis. Hypercholesterolemia was induced by a 4% cholesterol and 0.5% cholic acid diet, added to the normal rat diet. The cholesterol and cholic acid diet increased the level of serum total cholesterol from 1.3 +/- 0.0 to 4.8 +/- 0.9 (+/- SD) mmol/L and the level of low-density lipoprotein cholesterol from 0.3 +/- 0.0 to 2.6 +/- 1.0 mmol/L (p < 0.05) but caused no change in the level of high-density lipoprotein cholesterol, 1.0 +/- 0.1 versus 0.7 +/- 0.3 mmol/L. The level of plasma triglycerides remained also unchanged. Quantitation of two major chronic rejection-associated eicosanoids from the allograft vascular wall showed a significant increase in the synthesis of thromboxane B2 in the hyperlipidemic animals from 6.0 +/- 5.0 to 8.0 +/- 5.0 ng/mg dry weight and a slight reduction in the synthesis of 6-keto-prostaglandins F1 alpha. In vivo labeling of the recipient rat with tritiated thymidine and autoradiography showed that hypercholesterolemia did not affect the proliferation of inflammatory cells in the allograft adventitia, slightly increased the proliferation of smooth muscle cells in the media from 23 +/- 14 cells to 34 +/- 13 cells (+/- SEM) per cross section (p = ns), but slightly reduced the proliferation of smooth muscle cells in the intima from 13 +/- 6 to 6.2 +/- 1.5 (p = ns). Hypercholesterolemic recipients did not show any significant enhancement but, in fact, showed a delay in the generation of arteriosclerotic changes in the allograft intima. We conclude that although hypercholesterolemia, in the absence of hypertriglyceridemia, induces significant alterations in the eicosanoid metabolism and minor alterations in smooth muscle cell proliferation in the transplant vascular wall, it does not enhance arteriosclerotic alterations in chronically rejecting rat aortic allografts.

6-Ketoprostaglandin F1 alpha↗