A controlled serial ultrastructural tracer study of first-set cardiac allograft rejection in the rat. Evidence that the microvascular endothelium is the primary target of graft destruction.

In order to define the serial morphologic correlates of unmodified first-set cardiac allograft rejection in an inbred rat strain combination, a series of Wistar-Furth cardiac allografts transplanted to normal nonsensitized Lewis recipients were studied as a function of time with the use of well-documented ultrastructural tracer techniques. Colloidial carbon was employed as a vascular label for detection of microvascular endothelial structural alterations, and horseradish peroxidase was used as a tracer probe for localization of cell-membrane permeability dysfunction of allograft endothelium and cardiocytes as well as of elements of the cellular infiltrate. Wistar-Furth to Wistar-Furth syngeneic heart grafts and Wistar-Furth recipients' own hearts provided appropriate control data. This study was demonstrated that severe diffuse loss of functional and structural integrity of the microvascular endothelium precedes the development of extensive damage to cardiac muscle cells and thus provides strong evidence that the allograft microcirculation is the primary target of immunologic injury. In addition, the sequential pattern of injurious changes present in the rejecting allografts was similar to that observed in certain models of delayed-type hypersensitivity and of skin graft rejection, raising the possibility that lymphokine-mediated mechanisms may be of major pathogenetic significance in this setting.     

Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy

Late allograft rejection due to transplant vasculopathy continues to be a major clinical problem. Increasing the ratio of donor transplant size to recipient weight has been shown to reduce the incidence of late allograft failure. Using a murine pancreas transplant model we have tested the hypothesis that increasing the donor transplant size in a recipient can promote long-term allograft survival by promoting recovery from transplant vasculopathy. Recipients of an allograft that showed extensive vasculopathy were transplanted with a second donor transplant. The effect of the second allograft on the vasculopathy present in the first graft was measured. Transplanting a second allograft reversed all signs of ongoing rejection, including transplant vasculopathy, resulting in long-term survival of the first graft. Vasculopathy was only reversed if the first and second grafts were from the same mouse strain, suggesting an antigen-specific mechanism. However, the recovery of the first graft was not associated with antigen-specific peripheral tolerance.     

Endothelial and smooth muscle cells express leukocyte adhesion molecules heterogeneously during acute rejection of rabbit cardiac allografts.

Interactions of leukocytes with vascular wall cells figure prominently in acute rejection and development of vascular occlusive disease after cardiac transplantation. To investigate the time course and distribution among different types of vessels of expression of endothelial leukocyte adhesion molecules, issues difficult to address in humans, we studied heterotopic transplants of Dutch-Belted rabbit hearts into New Zealand white recipients without immunosuppression (average time to graft failure 8.2 +/- 0.4 days). We found constitutive expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) by coronary arterial endothelium in normal rabbits, whereas myocardial capillaries and the endocardial lining cells showed little or no expression of VCAM-1. VCAM-1 expression increased within 1 day after transplantation on the endothelium of the transplanted aorta and endocardium and on myocardial microvascular endothelial cells. ICAM-1 expression increased remarkably on all endothelia studied from 2 to 8 days after transplantation. Adhesion molecule expression on coronary artery endothelial cells also increased during severe allograft rejection (from a histological score of 1.7 +/- 0.6 pretransplant to 4.8 +/- 0.2 8 days after transplant for VCAM-1 and from 0.9 +/- 0.6 to 4.4 +/- 0.3 for ICAM-1, n = 43 arteries in 5 animals, mean +/- SD). In addition, coronary artery and aortic smooth muscle cells also showed induction of VCAM-1 and ICAM-1 8 days after transplant. We conclude that endothelial activation in a transplanted organ can occur rapidly and varies among microvascular, endocardial, and coronary artery endothelial cells, a point germane to the interpretation of endomyocardial biopsies. Augmented expression of adhesion molecules precedes temporally leukocyte accumulation in vessels. In addition, our finding of activation of coronary artery smooth muscle cells during acute rejection suggests that such episodes may contribute to the development of accelerated coronary arteriosclerosis.     

Anti-vimentin antibodies in transplant and disease

Non-HLA antibodies are recognized as a potential source of antibody mediated rejection following transplantation. The epitopes which lead to production of these antibodies are a result of tissue disruption, specifically endothelium, secondary to inflammation and injury. Vimentin is a cytoskeletal protein involved in many aspects of cellular organization, signaling, and proliferation. Recently, antivimentin antibodies have been shown to be important not only for rheumatological autoimmune diseases, but also cardiac and renal transplant dysfunction. In cardiac transplant recipients, antivimentin antibodies are associated with coronary artery vasculopathy and chronic graft loss. In renal transplantation, antivimentin antibodies are detected prior to transplantation and are also correlated with chronic graft dysfunction. In renal transplant recipients, antivimentin antibodies seen prior to transplantation are thought to be secondary to chronic endothelial injury during hemodialysis and therefore more prevalent prior to renal transplant than cardiac transplantation. In this review, we will examine the generation and pathogenesis of antivimentin antibodies. Given that these antibodies appear to be associated with both post-cardiac and -renal transplant dysfunction, developing standard detection paradigms may be important for risk stratification prior to transplantation. Finally, understanding the pathogenesis of antivimentin antibodies may lead to the development potential therapies in order to improve long-term survival.     

Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft

The recognition and acceptance of the entity of antibody-mediated rejection (AMR) of solid organs has been slow to develop. Greatest acceptance and most information relates to cardiac transplantation. AMR is thought to represent antibody/complement mediated injury to the microvasculature of the graft that can result in allograft dysfunction, allograft loss, accelerated graft vasculopathy, and increased mortality. The morphologic hallmark is microvascular injury with immunoglobulin and complement deposition in capillaries, accumulation of intravascular macrophages, and in more severe cases, microvascular hemorrhage and thrombosis, with inflammation and edema of the affected organ. Understanding of the pathogenesis of AMR, criteria and methods for diagnosis, and treatment strategies are still in evolution, and will be addressed in this review.     

Regulation of the CD4 T cell allo-immune response by endothelial cells

Recent studies have revealed the presence of pro-inflammatory and/or regulatory CD4⁺ T cells within allografts promoting either graft rejection or tolerance. Histological evidence has identified the microvascular endothelium as the primary site of allograft damage as it is the first site of encounter with the recipient’s immune system. The initial view of the human endothelial cell inducing an effector Th1 response leading to graft rejection has been extended by recent results which demonstrate the endothelial cell ability to generate other CD4⁺ T cell sub-populations including Th17 and Treg cells. In the transplantation setting, the allo-reactivity of the endothelium with the CD4⁺ T cell populations is likely to depend upon multiple factors including the vascular origin of the endothelial cell, the cytokine environment, the presence or absence of pro-inflammatory stimuli including ligands of Toll like receptors and alloantibodies. This review provides an update on the characteristics of the endothelial cell activation of the CD4⁺ T cell response and an analysis of the factors, which can modify this activity in favor of either graft rejection or tolerance.     

Ultrastructure as a diagnostic adjunct in the evaluation of lung allograft biopsies

Humoral immunity contributes significantly to lung graft dysfunction. Recognizing a role of ultrastructural studies in the evaluation and diagnosis of chronic humoral allograft rejection in the kidney, the authors sought to explore its utility as a diagnostic adjunct in lung allograft biopsies. Ultrastructural studies were conducted on 44 biopsies from 26 lung transplant recipients. Endothelial cell activation and necrosis were seen in the setting of acute humoral allograft rejection. Septal chronic vasculopathic changes of thickening and lamellation of the basement membrane zone (BMZ) and BMZ collagen deposition were correlated with greater numbers of humoral allograft rejection episodes and with the development of chronic graft dysfunction/bronchiolitis obliterans syndrome. There was a positive correlation between the extent of septal fibrosis and certain chronic vasculopathic changes, namely collagen deposition in the BMZ and BMZ wrinkling. Patients with chronic graft dysfunction and multiple rejection episodes manifested low diffusion capacities (less than 50% predicted). The results indicate that ultrastructural analysis is useful in identification of septal fibrosis and chronic vasculopathy of the septal microvasculature, correlating with chronic graft dysfunction, encompassing not only fibrotic sequelae of the bronchial wall but also irreversible terminal lung parenchymal changes, the latter associated with repeated episodes of humoral rejection.     

Antibody ligation of human leukocyte antigen class I molecules stimulates migration and proliferation of smooth muscle cells in a focal adhesion kinase-dependent manner

Chronic rejection manifests as transplant vasculopathy, which is characterized by intimal thickening of the vessels of the allograft. Intimal thickening is thought to result from the migration and proliferation of vascular smooth muscle cells (SMC) in the vessel media, followed by deposition of extracellular matrix proteins. The development of post-transplantation anti-human leukocyte antigen (HLA) antibodies (Ab) is strongly correlated with the development of transplant vasculopathy and graft loss. Here we demonstrate that cross-linking of HLA class I molecules on the surface of human SMC with anti-HLA class I Ab induced cell proliferation and migration. Class I ligation also increased phosphorylation of focal adhesion kinase (FAK), Akt, and ERK1/2 in SMC. Knockdown of FAK by siRNA attenuated class I-induced phosphorylation of Akt and ERK1/2, as well as cell proliferation and migration. These results indicate that ligation of HLA class I molecules induces SMC migration and proliferation in a FAK-dependent manner, which may be important in promoting transplant vasculopathy.     

Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability

Appreciation of the glomerular microcirculation as a specialized microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface-anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the transcapillary escape of water and macromolecules, acting as an integral component of the multilayered barrier provided by the walls of these microvessels (ie acting in concert with clefts or fenestrae across endothelial cell layers, basement membranes and pericytes). Dysfunction of any of these capillary wall components, including the endothelial glycocalyx, can disrupt normal microvascular permeability. Because of its ubiquitous nature, damage to the endothelial glycocalyx alters the permeability of multiple capillary beds: in the glomerulus this is clinically apparent as albuminuria. Generalized damage to the endothelial glycocalyx can therefore manifest as both albuminuria and increased systemic microvascular permeability. This triad of altered endothelial glycocalyx, albuminuria and increased systemic microvascular permeability occurs in a number of important diseases, such as diabetes, with accumulating evidence for a similar phenomenon in ischaemia-reperfusion injury and infectious disease. The detection of albuminuria therefore has implications for the function of the microcirculation as a whole. The importance of the endothelial glycocalyx for other aspects of vascular function/dysfunction, such as mechanotransduction, leukocyte-endothelial interactions and the development of atherosclerosis, indicate that alterations in the endothelial glycocalyx may also be playing a role in the dysfunction of other organs observed in these disease states.     

Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities

The endothelium is essential for the maintenance of vascular homeostasis. Central to this role is the production of endothelium-derived nitric oxide (EDNO), synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelial dysfunction, manifested as impaired EDNO bioactivity, is an important early event in the development of various vascular diseases, including hypertension, diabetes, and atherosclerosis. The degree of impairment of EDNO bioactivity is a determinant of future vascular complications. Accordingly, growing interest exists in defining the pathologic mechanisms involved. Considerable evidence supports a causal role for the enhanced production of reactive oxygen species (ROS) by vascular cells. ROS directly inactivate EDNO, act as cell-signaling molecules, and promote protein dysfunction, events that contribute to the initiation and progression of endothelial dysfunction. Increasing data indicate that strategies designed to limit vascular ROS production can restore endothelial function in humans with vascular complications. The purpose of this review is to outline the various ways in which ROS can influence endothelial function and dysfunction, describe the redox mechanisms involved, and discuss approaches for preventing endothelial dysfunction that may highlight future therapeutic opportunities in the treatment of cardiovascular disease.     

肾移植及移植后的血管并发症

背景：尽管肾移植手术技术已相当成熟,但各移植中心难免会出现术中及术后的血管并发症。 目的：分析肾移植过程中及移植后血管并发症的诊断与处理。 方法：回顾性分析 11 例肾移植过程中、移植后血管并发症资料。移植过程中并发症：动脉吻合口狭窄2例,肾静脉横断1例,髂外动脉硬化斑块剥脱堵塞肾动脉3例,移植肾静脉扭曲1例;移植后并发症：肾外型假性动脉瘤2例,吻合口狭窄1例,移植肾动脉压迫梗阻1例。 结果与结论：肾移植中吻合口狭窄2例移植后恢复良好,分别于移植后6年及11年移植肾失功;肾静脉横断1例随访12年移植肾失功;髂外动脉硬化斑块剥脱堵塞肾动脉3例,1例移植肾当即失功,另2例分别随访6年及2年,现移植肾功能良好;移植肾静脉扭曲1例移植后出现移植肾功能延迟恢复,1个月后因重症肺部感染死亡。移植后发生的血管并发症中肾外型假性动脉瘤2例移植肾均失功;吻合口狭窄1例经置入支架后肾功能恢复正常,已随访18个月;移植肾动脉压迫梗阻1例移植后出现移植肾功能延迟恢复,3周后因重症肺部感染死亡。结果说明肾移植过程中及移植后发生血管并发症,只要诊断准确、处理及时,可取得比较满意的治疗效果。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Blood pressure regulation VIII: resistance vessel tone and implications for a pro-atherogenic conduit artery endothelial cell phenotype

Dysfunction of the endothelium is proposed as the primary initiator of atherosclerotic peripheral artery disease, which occurs mainly in medium- to large-sized conduit arteries of the lower extremities (e.g., iliac, femoral, popliteal arteries). In this review article, we propose the novel concept that conduit artery endothelial cell phenotype is determined, in part, by microvascular tone in skeletal muscle resistance arteries through both changes in arterial blood pressure as well as upstream conduit artery shear stress patterns. First, we summarize the literature supporting the involvement of sympathetic nerve activity (SNA) and nitric oxide (NO) in the modulation of microvascular tone and arterial blood pressure. We then focus on the role of elevated blood pressure and shear stress profiles in modulating conduit artery endothelial cell phenotype. Last, we discuss findings from classic and emerging studies indicating that increased vascular resistance, as it occurs in the context of increased SNA and/or reduced NO bioavailability, is associated with greater oscillatory shear stress (e.g., increased retrograde shear) in upstream conduit arteries. The ideas put forth in this review set the stage for a new paradigm concerning the mechanistic link between increased microvascular tone and development of conduit artery endothelial dysfunction and thus increased risk for peripheral artery disease. Indeed, a vast amount of evidence supports the notion that excessive blood pressure and oscillatory shear stress are potent pro-atherogenic signals to the endothelium.     

Lichen sclerosus: A C5B-9 mediated chronic microvascular injury syndrome potentially reflective of common adult comorbidities

Lichen sclerosus (LS) is a cutaneous disease of unknown etiology that often involves the vulva or foreskin but also can affect extragenital sites. Regardless of the anatomic site, the histomorphology and presumably pathogenesis are similar. Perhaps a clue to the pathophysiology of LS lies in its frequent association with morphea, specifically, when occurring in an extragenital context. In our experience a striking feature evident in established lichen sclerosis (LS) is one of superficial vascular drop out whereby residual vessels exhibited endothelial cell necrosis and microvascular basement membrane zone thickening, the latter reflective of antecedent episodes of microvascular injury. We sought to understand the pathophysiology that underlies the distinct vascular changes and in doing so, shed light on the pathogenesis of LS. We examined 44 cases of LS over a period of 2019 to 2021. We were able to obtain past medical histories in 34 of the 44 cases. Regarding pathological assessment, the predominant focus was on microvascular changes. We assessed the role of C5b-9 mediated vascular injury in the pathogenesis of the vasculopathy and enhanced type I interferon signaling in vessels given the morphologic semblance to the select interferonopathy syndromes, namely fibrosing dermatomyositis and Kohlmeier Degos disease. We examined the expression of CMV DNA and protein based on prior observations in an earlier study that isolated early protein expression in the microvasculature in the setting of LS and scleroderma. From a clinical perspective, the most striking association was an older age at the time of diagnosis (mean age of 62 years and median age of 61.5 years) and the presence of vascular comorbidities of diabetes, hypertension, and hyperlipidemia in almost 80% of cases. All cases showed significant microvascular changes in the superficial corium with the most frequent findings being those of significant basement membrane zone reduplication and vascular drop out. A number of cases showed prominent microvascular deposits of C5b-9 in the zone of hyalinizing fibrosis or subjacent to the discernible table of fibroplasia in the absence of enhanced type I interferon signaling. In no case were there viral cytopathic changes associated with CMV affecting the endothelium. The studies that encode CMV DNA or protein did not show a significant role for CMV reactivation in endothelium in the majority of the studied cases. It is concluded that the pathophysiology of LS includes a microvascular injury syndrome within the papillary dermis. The mechanism of endothelial cell injury is complement mediated at least in part and could reflect an adaptive immune response targeting endothelium indicative of classic complement pathway activation when coexisting with morphea or occurring in younger individuals. A non-immune based endothelial dysfunction and complement mediated injury unrelated to antibody driven classic complement pathway activation are more likely pathogenetically in the setting of certain diseases like diabetes mellitus and hypertension. Vascular drop out can be explained by the diminished endothelial progenitor pool needed to repopulate the damaged microvessels in certain settings like hypertension and diabetes.     

COMMENT TO: GASTRIC CARCINOMAS WITH UNUSUAL CYTOPLASMIC ULTRASTRUCTURAL FEATURES

Accelerated arteriosclerosis secondary to chronic allograft rejection is a major long-term complication of heart transplantation. Accelerated arteriosclerosis has been associated with an endothelialitis, and the majority of the involved inflammatory cells are T lymphocytes and macrophages. Coronary arteries from six heart allograft recipients with transplantrelated arteriosclerosis were examined by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Four hearts were explants from heart transplant recipients with severe accelerated arteriosclerosis who were undergoing retransplantation, and two were obtained from autopsied recipients. The patients ranged in age from 6 to 60 years (mean, 44 years). The graft survival for these six hearts ranged from 1.4 to 5.6 years (mean, 4.3 years). Lymphocytes, macrophages, and smooth muscle cells were identified by TEM in the intimas of all the vessels examined. The lymphocytes were often in contact with macrophages or in close proximity to injured endothelial cells. Areas of endothelial injury were characterized by vacuolization of endothelial cells and partial denudation of the endothelium with fibrin deposition. SEM also revealed endothelial cell injury with disorganization of the endothelium and gaps between endothelial cells. Leukocytes and platelets were often noted in these gaps. These findings suggest that accelerated arteriosclerosis in heart transplant recipients is associated with an accumulation of macrophages, lymphocytes, and smooth muscle cells in the intima as well as with lymphocyte-directed endothelial injury.     

Do alloreactivity and prolonged cold ischemia cause different elementary lesions in chronic allograft nephropathy?

This study assesses the individual contributions of the nonalloreactive factor, cold ischemia (CI), and alloreactivity to late functional and structural renal graft changes, and examines the effect of the association of both factors on the progression of chronic allograft nephropathy. Lewis rats acted as receptors of kidneys from either Lewis or Fischer rats. For CI, kidneys were preserved for 5 hours. The rats were divided into four groups: Syn, syngeneic graft; SynI, syngeneic graft and CI; Allo, allogeneic graft; AlloI, allogeneic graft and CI. Renal function was assessed every 4 weeks for 24 weeks. Grafts were evaluated for acute inflammatory response at 1 week and for chronic histological damage at 24 weeks. Only when CI and allogenicity were combined did immediate posttransplant mortality occur, while survivors showed accelerated renal insufficiency that induced further mortality at 12 weeks after transplant. Solely ischemic rats developed renal insufficiency. Renal structural damage in ischemic rats was clearly tubulointerstitial, while significant vasculopathy and glomerulosclerosis appeared only in the allogeneic groups. There was increased infiltration of macrophages and expression of mRNA-transforming growth factor-beta1 in the ischemic groups, irrespective of the allogeneic background. The joint association of CI plus allogenicity significantly increased cellular infiltration at both early and late stages, aggravating tubulointerstitial and vascular damage considerably. In summary, CI is mainly responsible for tubulointerstitial damage, whereas allogenicity leads to vascular lesion. The association of both factors accelerates and aggravates the progression of experimental chronic allograft nephropathy.     

HLA Class I: An unexpected role in integrin β4 signaling in endothelial cells

The production of anti-donor antibodies to HLA class I and class II antigens following transplantation is associated with development of transplant vasculopathy and graft loss. Antibodies against HLA class I (HLA-I) molecules are thought to contribute to transplant vasculopathy by triggering signals that elicit the activation and proliferation of endothelial cells. The proximal molecular events that regulate HLA-I dependent signal transduction are not well understood. We demonstrated a mutual dependency between HLA-I and integrin β4 to stimulate signal transduction and cell proliferation. Similarly, we found that integrin β4-mediated cell migration was dependent upon its interactions with HLA-I molecules. Since integrin β4 has been implicated in angiogenesis and tumor formation, associations between integrin β4 and HLA-I may play an important role in cancer. Further characterization of interactions between HLA-I and integrin β4 may lead to the development of therapeutic strategies for the treatment and prevention of chronic allograft rejection and cancer.     

IL-4 expression delays eosinophil-independent vasculopathy and fibrosis during allograft rejection in the mouse

Transplant vasculopathy in the mouse is thought to be dependent on IL-4 and mediated by IL-5 and eosinophils, whereas in the rat and human systems, IL-4 is associated with the absence of transplant vasculopathy and down-regulation of a Th1-type response. In this study we tested the possibility that the apparent difference in the role of IL-4 in transplant vasculopathy is related to protocol differences rather than to the species being studied. Using a protocol that closely resembles that used in rat and human studies, we developed a model of transplant vasculopathy in the mouse that is associated with Th1-type cytokines and independent of IL-5 and eosinophil infiltration. In this model IL-4 promotes a significant delay in vasculopathy in the graft (P = 0.04) and a decrease in the incidence of allograft rejection (P = 0.02). The data suggest that the role of IL-4 in transplant vasculopathy can be controlled by the protocol used to treat the transplant recipient.     

New developments in renal transplant pathology

The renal transplant biopsy plays a central role in the diagnosis of renal allograft dysfunction; in particular in differentiating immune-mediated rejection from various infective, ischaemic and toxic pathologies. Recent advances have been made in refining the histological criteria for rejection diagnosis. The Banff’97 classification of renal allograft pathology has gained almost universal acceptance. In this classification, acute rejection is divided into three main types, tubulointerstitial, vascular and severe vascular, that differ in response to anti-rejection therapy and long-term prognosis. There remain, however, a number of challenges; interpretation of biopsies showing borderline changes, the diagnosis of humoral rejection and differentiating rejection from interstitial nephritis associated with viral infections present specific problems. There are potential applications for new molecular and immunohistochemical techniques in these areas. Other challenges arise from the application of the Banff classification. Recent validation studies have indicated that the reproducibility of some Banff criteria is low and that there are a number of histological features, not included in the Banff schema, that may be useful in rejection diagnosis.New roles for the transplant biopsy are developing in the management of patients with stable graft function, as indicated by measurement of serum creatinine. Protocol biopsies performed at regular intervals in the early post-transplant period may be used to predict subsequent development of chronic allograft nephropathy, the major cause of graft loss. The interpretation of these biopsies may be refined using morphometric techniques and immunohistochemistry for cytokines and matrix components. Protocol biopsies may also be used to diagnose sub-clinical rejection, and early evidence indicates that treatment of these histological rejections improves long-term graft outcome. The role of the transplant biopsy will continue to evolve with greater use of organs from marginal donors, improved understanding of the processes of graft injury and fibrosis, and the introduction of new immunosuppressive regimens.     

Learning from rejection: What transplantation teaches us about (other) vascular pathologies

Allograft vasculopathy is an accelerated intimal hyperplastic lesion leading to progressive vascular stenosis; it represents the major long-term limitation to successful solid organ transplant. Although allograft vasculopathy is not formally an autoimmune disease, nor does it constitute a major cause of cardiovascular disease on a purely numerical basis, its pathogenesis provides an important window on the mechanisms by which immune injury can drive more common vascular pathologic entities. Thus, insights gleaned from vascularized solid organ transplants can shed new mechanistic (and therapeutic) light on: 1) the intimal vascular responses accompanying typical atherosclerosis and other inflammatory vessel diseases (e.g., scleroderma); 2) the pathogenesis of vascular stenosis versus aneurysm formation; 3) the sources of intimal smooth muscle cells in the healing of any vascular injury; and 4) the mechanisms by which smooth muscle cells are recruited into intimal lesions. Indeed, research on allograft vasculopathy has led to the understanding that interferon-γ plays a similar pathogenic role in a host of vascular stenosing lesions—and that Th2 cytokines can drive vascular remodeling and aneurysm formation. Moreover, circulating precursors (and not just medial smooth muscle cells) contribute to the intimal hyperplasia seen in atherosclerosis and in-stent restenosis. That non-vessel smooth muscle cells can be recruited to sites of vessel injury further suggests that chemokine and adhesion molecule interactions may be viable targets to limit vascular stenosis in a wide range of vascular lesions. This review will describe the pathogenesis of allograft vasculopathy, and will relate how understanding the underlying pathways informs our understanding of both human transplant-associated disease, as well as other human vascular pathologies.     

Exercise after heart transplantation

Exercise intolerance in heart transplant recipients (HTR) has a multifactorial origin, involving complex interactions among cardiac, neurohormonal, vascular, skeletal muscle and pulmonary abnormalities. However, the role of these abnormalities may differ as a function of time after transplantation and of many other variables. The present review is aimed at evaluating the role of cardiac, pulmonary and muscular factors in limiting maximal aerobic performance of HTR, and the benefits of chronic exercise. Whereas pulmonary function does not seem to affect gas exchange until a critical value of diffusing lung capacity is attained, cardiac and skeletal muscle function deterioration may represent relevant factors limiting maximal and submaximal aerobic performance. Cardiac function is mainly limited by chronotropic incompetence and diastolic dysfunction, whereas muscle activity seems to be limited by impaired oxygen supply as a consequence of the reduced capillary network. The latter may be due to either immunosuppressive regimen or deconditioning. Endurance and strength training may greatly improve muscle function and maximal aerobic performance of HTR, and may also reduce side effects of immunosuppressive therapy and control risk factors for cardiac allograft vasculopathy. For the above reasons exercise should be considered an important therapeutic tool in the long-term treatment of heart transplant recipients.