Graft Vessel Disease Research Articles

Role of growth factors in graft vessel disease

Role of growth factors in graft vessel disease

Preclinical models of chronic rejection: promises and pitfalls

C HRONIC rejection is a frequent cause of late graft loss. A prominent histopathologic component of chronic rejection is vessel wall proliferation and luminal narrowing, commonly referred to as graft vessel disease or transplant vasculopathy. The mechanisms of transplant vasculopathy arc complex, hence multiple approaches for its prevention or treatment are needed. In preclinical research a number of models are available that encompass targeting the immunologic processes as well as the vascular remodelling. The nonimmunological aspects of vascular remodelhng have been studied in a rat model of balloon angioplasty, although this model is not without pitfalls, as described in what follows. To study vascular remodelling triggered by immune mechanisms, allotransplantation of an abdominal aortic or carotid artcry segment is used. In this model, there is no acute rejection, as there is no parenchyma attached to these vessels. In syngcncic strain combinations, vessel transplantation allows study of nonimmunologic factors such as ischemiaircpcrfusion injury. Howcvcr, these models have the disadvantage that the grafted vessel differs in anatomy and diamctcr from the vessels in transplanted organs atfected by chronic rcjcction. Therefore, solid organ transplantation is the ultimate model for chronic rejection. In the following sections we describe some fcaturcs of the models of carotid balloon angioplasty and kidney allografting used to study chronic rejection.

Some new aspects of molecular mechanisms of cyclosporin A effect on immune response.

A few protein targets were found to display a specific high-affinity interaction with the immunosuppressant cyclosporin A (CsA): cytosolic cyclophilins (CyP)A, B, C, D, E containing from 122 to 174 amino acid residues in a polypeptide chain, and secreted forms of CyP; CyP-40, 40-kDa CsA-binding polypeptide complexed with steroid receptor (SR); CyP-related 150-kDa receptor of natural killer (NK) cells; interleukin 8 (IL-8); actin; a family of molecular chaperones hsp70 and P-glycoprotein (P-GP). All CyPs possess peptidyl-prolyl cis-trans isomerase activity (PPIase) and may serve as ATP-independent molecular chaperone proteins. The CsA-CyP complexes are specific inhibitors of Ca(2+)-and calmodulin-dependent protein phosphatase calcineurin (CaN). The inhibition of CaN blocks the activation of genes of IL-2, IL-2R, IL-4, etc. in T cells. In addition, immunosuppressive and/or antiinflammatory activity of CsA can be executed via CyP-40 and hsp 70 complexed with SR, and following the interaction with CyP-related receptor of NK and with IL-8. CsA binding to CyPC, P-GP and actin may throw light on the biochemical events leading to nephrotoxicity and graft vessel disease, two major side effects produced by CsA. The discovery of the interaction of human immunodeficiency virus type 1 (HIV-1) Gag protein with CyP and effective disruption of this interaction by CsA may be important for our understanding of the pathology caused by this immunosuppressive virus and will inspire therapeutic strategies to nip HIV in the bud. Bacterial immunophilins (ImPs) contribute to the virulence of pathogenic microorganisms. Elucidation of molecular mechanisms of microbial ImPs' action in the pathogenesis of bacterial infections may lead to new strategies for designing antibacterial drugs.

Identification of recurrent ischemia after coronary artery bypass surgery: a comparison of positron emission tomography and single photon emission computed tomography

Current techniques for the detection of recurrent coronary stenoses following bypass grafting have shown disappointing diagnostic accuracy. This study used the same dipyridamole-handgrip stress to compare the accuracy of rubidium-82 positron emission tomography and thallium-201 single photon emission computed tomography, in 50 consecutive post-bypass patients undergoing coronary arteriography at a mean interval of 6.5 years after surgery. Significant stenoses in native coronary vessels (> 50% diameter) or grafts (> 70% diameter) were defined by quantitative angiography. Forty-six patients had recurrent or residual stenoses, 43 (93%) had a perfusion defect identified by positron emission tomography, and 35 (76%) were identified by single photon emission computed tomography ( P = 0.04). Fourteen of the 17 patients (82%) without previous Q-wave myocardial infarction were identified by positron emission tomography; 10 of the 17 (59%) were detected by single photon emission computed tomography ( P = NS). Stress-induced perfusion defects were demonstrated by positron emission tomography in 19 patients; of this group, thallium imaging identified reversible defects in 11, showed no perfusion defect in 1, and portrayed a persistent defect in 7 patients. Significant graft disease was present in 33 patients; perfusion defects were identified by positron emission tomography in 30 (91%), and by single photon emission computed tomography in 24 (73%, P = NS). Four patients were fully revascularized, without significant recurrent coronary disease; normal perfusion was present in 3 (75%) by positron emission tomography, and 4 (100%) by single photon emission computed tomography. Myocardial perfusion imaging using positron emission tomography has a high accuracy for the detection of both graft and native vessel disease, and may be useful in the non-invasive follow-up of patients following coronary artery bypass grafting.

Effects of cyclosporin, FK506, and rapamycin on graft-vessel disease

Graft-vessel disease (GVD) limits the long-term survival of heart-transplant patients, and this effect has not been altered by use of cyclosporin for immunosuppression. We compared the effects of the immunosuppressants cyclosporin, FK506, and rapamycin on GVD in a rat-heart transplantation model. Allografted hearts from rats treated with 1 mg/kg FK506 for 50 days showed the same degree of myocardial rejection but a significantly worse (p<0·05) grade of GVD compared with grafted hearts from rats treated with 1·5 mg/kg cyclosporin for the same time. 2 mg/kg FK506 for 50 days prevented cellular rejection but GVD was as severe as that found with 1 mg/kg FK506. Moderate GVD was present in two of five allografted hearts after treatment with 4 mg/kg FK506. 1·5 mg/kg rapamycin for 50 days was an effective inhibitor of rejection and GVD. Based on our results in rats, the possibility that GVD may occur in human heart-transplant recipients treated with FK506 cannot be excluded.

Dose Response of Fish Oil Versus Safflower Oil on Graft Arteriosclerosis in Rabbit Heterotopic Cardiac Allografts

With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7.9 +/- 1.9 microns versus 34.0 +/- 13.0 microns, analysis of variance: p = 0.054). Low-dose safflower oil also had a slight, but nonsignificant, beneficial effect on graft vessel disease when compared to control rabbits. The same trends were observed in the degree of histologic rejection (0 = none to 3 = severe) in fish oil- and safflower oil-treated animals. Rejection score correlated weakly but significantly (p = 0.0001) with mean luminal occlusion (r = 0.52) and intimal thickness (r = 0.46). Therefore allograft coronary disease in this model appeared to exhibit an unfavorable, direct-dose response to fish oil and safflower oil, independent of effects on plasma lipids.(ABSTRACT TRUNCATED AT 400 WORDS)