Pattern specification and immune response transcriptional signatures of pericardial and subcutaneous adipose tissue.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States. Recent studies suggest that pericardial adipose tissue (PCAT) secretes inflammatory factors that contribute to the development of CVD. To better characterize the role of PCAT in the pathogenesis of disease, we performed a large-scale unbiased analysis of the transcriptional differences between PCAT and subcutaneous adipose tissue, analysing 53 microarrays across 19 individuals.

Autoimmune sensitization to cardiac myosin leads to acute rejection of cardiac allografts in miniature swine.

Background: Recent studies in mice and patients suggest that posttransplantation induction of autoimmune responses to tissue-specific antigens contributes to the rejection of major histocompatibility complex mismatched allotransplants. The relevance of this phenomenon to the rejection of major and minor histocompatibility-mismatched allografts performed in large-animal models remains to be established.

Methods: Miniature swine were immunized with cardiac myosin (CM) in Freund's adjuvant and received heterotopic, minor antigen-mismatched heart transplants.

Immunosuppression for lung transplantation.

As a result of advances in surgical techniques, immunosuppressive therapy, and postoperative management, lung transplantation has become an established therapeutic option for individuals with a variety of end-stage lung diseases. The current 1-year actuarial survival rate following lung transplantation is approaching 80%. However, the 5- year actuarial survival rate has remained virtually unchanged at approximately 50% over the last 15 years due to the processes of acute and chronic lung allograft rejection (1).

Repetitive gastric aspiration leads to augmented indirect allorecognition after lung transplantation in miniature swine.

Introduction: Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition.

Methods: Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A.

In primed allo-tolerance, TIM-3-Ig rapidly suppresses TGFbeta, but has no immediate effect on Foxp3.

T-cell immunoglobulin mucin-3 (TIM-3) is only expressed by differentiated TH1 cells following their proliferative response to antigen, functioning to terminate TH1-mediated immunity upon binding to the TIM-3 ligand, galectin-9. This critical regulatory process involves Treg cells via their stable expression of galectin-9. Soluble TIM-3-Ig blocks galectin-9 and prevents induction of peripheral tolerance.

Mechanisms of chronic rejection in cardiothoracic transplantation.

Despite significant improvements in early post-transplantation survival rates, long-term patient and graft survival have remained poor, due in large part to the vexing problem of chronic allograft rejection. Attempts to combat this problem with intensification of immunosuppression have led to concomitant increases in the rates of fatal malignancies and infections. In cardiac transplantation, chronic rejection is manifested primarily by a disease entity known as cardiac allograft vasculopathy, an occlusive narrowing of the coronary vessels.

Regulatory transplantation tolerance and "stemness": evidence that Foxp3 may play a regulatory role in SOCS-3 gene transcription.

Immune self-tolerance is controlled by a subset of T lymphocytes that are regulatory (Treg) and epigenetically programmed to suppress autoreactive immune effector cells in vivo. Treg require expression of Foxp3, a transcription factor that not only represses the interleukin-2 gene promoter, but also sequesters key mediators of T-cell signal transduction by complexing with cytoplasmic NFAT and NFkappaB. We have discovered that expression of Foxp3 is linked to two stem cell-related factors, namely leukemia inhibitory factor (LIF) and axotrophin.

Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance.

In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen.

A systematic review of randomized trials comparing revascularization rate and graft patency of off-pump and conventional coronary surgery.

Objective: Although many trials have been conducted to evaluate the benefits of off-pump coronary surgery, few have concentrated on graft patency. We sought to evaluate the impact of off-pump surgery on completeness of revascularization and graft patency compared with conventional surgery.

Methods: A systematic literature search was undertaken of all randomized trials of off-pump coronary surgery in MEDLINE, EMBASE, the Cochrane Library Controlled Trials Register, the National Research Register, and abstracts from major conferences.

Vascular endothelium does not activate CD4+ direct allorecognition in graft rejection.

Expression of MHC class II by donor-derived APCs has been shown to be important for allograft rejection. It remains controversial, however, whether nonhemopoietic cells, such as vascular endothelium, possess Ag-presenting capacity to activate alloreactive CD4(+) T lymphocytes. This issue is important in transplantation, because, unlike hemopoietic APCs, allogeneic vascular endothelium remains present for the life of the organ.

Fetal liver as a source of autologous progenitor cells for perinatal tissue engineering.

Mesenchymal progenitor cells, isolated from adult bone marrow, have been shown to have utility for autologous tissue engineering. The possibility of isolating from the fetal hematopoietic system a cell population with similar potential, which could be used for autologous reconstruction of prenatally diagnosed congenital anomalies, has not been explored to date. Liver stromal cells isolated from a portion of the right lateral hepatic lobe of midgestation fetal lambs were expanded in vitro.

Surrogate markers and risk factors for chronic lung allograft dysfunction.

Obliterative bronchiolitis (OB) is the histologic correlate of chronic allograft dysfunction in pulmonary transplantation. The histologic diagnosis of OB is challenging, therefore a physiologic definition, bronchiolitis obliterans syndrome (BOS) based on pulmonary function tests has been used as a surrogate marker for OB for the last decade. BOS has proven to be the best available surrogate marker for OB and is predictive of the ultimate endpoints of graft and patient survival.

Homeostatic proliferation is a barrier to transplantation tolerance.

Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia.

Clinical risk factors for primary graft failure following lung transplantation.

Study Objective: s: Primary graft failure (PGF) is a devastating acute lung injury syndrome following lung transplantation. We sought to identify donor, recipient, and operative risk factors for its development.

Design: We conducted a cohort study of 255 consecutive lung transplant procedures performed between October 1991 and July 2000.

Hormonal resuscitation yields more transplanted hearts, with improved early function.

Background: Brain death results in cardiovascular instability and poor organ perfusion in many brain-dead donors. Hormonal resuscitation stabilizes certain brain-dead donors and is associated with significant increases in the numbers of organs transplanted per donor. The goal of this study was to examine the quality of hearts recovered from donors treated with hormonal resuscitation.

Temporal changes in left ventricular systolic function in heart donors: results of serial echocardiography.

Background: Heart donor availability continues to limit cardiac transplantation rates and many donor hearts are not transplanted because of left ventricular dysfunction. The aim of this study was to determine whether intensive donor management results in improved left ventricular systolic function as measured by serial echocardiography.

Methods: Using the California Transplant Donor Network Database, all donors who underwent serial echocardiography during donor management (from 1996 to 2000) were identified.

Aggressive pharmacologic donor management results in more transplanted organs.

Background: Brain death results in adverse pathophysiologic effects in many cadaveric donors, resulting in cardiovascular instability and poor organ perfusion. Hormonal resuscitation (HR) has been reported to stabilize and improve cardiac function in brain-dead donors. The goal of this study was to examine the effect of HR on the brain-dead donor on the number of organs transplanted per donor.

Mouse vascular endothelium activates CD8+ T lymphocytes in a B7-dependent fashion.

Despite several studies examining the contribution of allorecognition pathways to acute and chronic rejection of vascularized murine allografts, little data describing activation of alloreactive T cells by mouse vascular endothelium exist. We have used primary cultures of resting or IFN-gamma-activated C57BL/6 (H-2(b)) vascular endothelial cells as stimulators and CD8(+) T lymphocytes isolated from CBA/J (H-2(k)) mice as responders. Resting endothelium expressed low levels of MHC class I, which was markedly up-regulated after activation with IFN-gamma.

Mechanism of T cell-mediated endothelial apoptosis.

Background: Cytotoxic T lymphocyte (CTL)-mediated destruction of allogeneic vascular endothelium is important in the pathogenesis of both acute and chronic allograft rejection. Despite the importance of this phenomenon, the effector mechanisms responsible for endothelial cell killing are not well defined, and conflicting conclusions have been reached based on variation in experimental methodology.

Methods: We used a recently described method for isolating mouse vascular endothelium to evaluate endothelial cell lysis by CTLs.

Increased transplanted organs from the use of a standardized donor management protocol.

The organ shortage has resulted in increasing recipient waiting lists and waiting-list deaths. The increased use of expanded donors has been associated with increased discarding of procured organs because of poor organ function. A structured donor management algorithm or critical pathway was tested to determine its effect on the donor management and procurement process.

Left ventricular assist device for right side assistance in patients with transposition.

Right (systemic) ventricular dysfunction is well described after Senning operations for transposition of the great arteries, and patients with congenitally corrected transposition of the great arteries. Transplantation remains the only definitive therapy for refractory heart failure, however patients may deteriorate clinically prior to the availability of a donor heart. This report details the implantation of a TCI Heartmate (Thoratec Corp.

Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28-29, 2001, Crystal City, Va.

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to approximately 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond approximately 2500 per year, the transplant waiting list mortality rate remains substantial.

Cardiopulmonary bypass for bilateral sequential lung transplantation in patients with chronic obstructive pulmonary disease without adverse effect on lung function or clinical outcome.

Objective: The use of cardiopulmonary bypass in lung transplantation remains controversial. Previous studies have concluded that cardiopulmonary bypass is deleterious, but these studies were confounded by the inclusion of patients with different diagnoses undergoing single- and double-lung transplantation with elective or emergency use of bypass. The goal of this study was to determine whether cardiopulmonary bypass has deleterious effects on lung function or clinical outcome by analyzing the cases of patients with a single disease entity and elective use of bypass for bilateral sequential lung transplantation.