Chronic Allograft Vasculopathy Research Articles

Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation.

Chronic allograft vasculopathy (CAV) limits the lifespan of pediatric heart transplant recipients. We investigated blood markers of inflammation, endothelial dysfunction, and damage to both the native and transplanted vasculature in children after heart transplantation. Serum samples were taken from pediatric heart transplant recipients for markers of inflammation and endothelial activation. The systemic vasculature was investigated using brachial artery flow-mediated dilatation and carotid artery intima-medial hyperplasia. CAV was investigated using intravascular ultrasound. Mean intima-media thickness (mIMT) > 0.5 mm was used to define significant CAV. Forty-eight children (25 male) aged 8-18 years were enrolled in the study. Patients were a median (interquartile range) 4.1 (2.2-8.7) years after transplant. Patients had increased levels of circulating IL6 (3.86 [2.84-4.95] vs. 1.66 [1.22-2.63] p < 0.0001), vascular cell adhesion molecule 1 (539 [451-621] vs. 402 [342-487] p < 0.001), intracellular adhesion molecule 1 305 (247-346) vs. 256 (224-294) p = 0.002 and thrombomodulin (7.1 [5.5-8.1] vs. 3.57 [3.03-4.71] p < 0.0001) and decreased levels of tumor necrosis factor-α, E selectin, and P selectin, compared with controls. The systemic vasculature was unaffected. Patients with severe CAV had raised serum von Willebrand factor and decreased serum thrombomodulin. Posttransplant thrombomodulin levels are elevated after transplant but significantly lower in those with mIMT > 0.5 mm. This suggests that subclinical inflammation is present and that natural anticoagulant/thrombomodulin activity is important after transplant.

SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy.

Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0±0.1 vs. 1.8±0.1, P<0.001 AoTx; 0.35±0.05 vs. 1.13±0.27, P<0.05 HTx). In vitro treatment of primary vascular smooth muscle cells with NOX-A12 showed a significant reduction in proliferation (0.42±0.04 vs. 0.24±0.03, P<0.05). TGF-β, TNF-α and IL-6 levels were significantly reduced under SDF-1 inhibition (3.42±0.37 vs. 1.67±0.33, P<0.05; 2.18±0.37 vs. 1.0±0.39, P<0.05; 2.18±0.26 vs. 1.6±0.1, P<0.05). SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes.

Abstract 417: Endosome-Based Activation of Non-Canonical NF-kB Signaling by Complement Membrane Attack Complexes

Using sera from transplant patients with high-titer panel reactive antibody (PRA), we previously described a model for studying the effects of alloantibody binding and complement activation on human endothelial cells (EC). With this model we found that complement membrane attack complexes (MAC) induced rapid post-translational stabilization of NF-kB-inducing kinase (NIK), the activator of non-canonical NF-kB signaling, which was required for inflammatory changes in cultured human EC and for vasculopathic changes in human coronary artery segments implanted into immunodeficient mouse hosts. To elucidate the mechanism of NIK stabilization, we performed a genome-wide siRNA screen and discovered a novel, TRAF3-independent signaling mechanism in which MAC induces NIK stabilization on endosomes. MAC is internalized by EC in a clathrin-, AP2-, and dynamin-dependent mechanism into Rab5+ endosomes. Activated Akt is recruited in a Rab5-dependent manner to the same endosomes which then bind and stabilize NIK and subsequently recruit and activate IKK-alpha, the catalytic activator of p52/RelB complexes, the non-canonical form of NF-kB. Pharmacological inhibition of MAC endocytosis blocked this pathway both in cultured EC and in human coronary artery xenografts. These data reveal a novel endosome-based signaling cascade for activating non-canonical NF-kB and identify new targets for inhibiting complement-mediated tissue injury such as chronic antibody-mediated rejection and cardiac allograft vasculopathy.

Twelve-month efficacy and safety of the conversion to everolimus in maintenance heart transplant recipients.

To determine the clinical reasons for conversion to everolimus (EVL) and long-term outcomes in heart transplant (HT) recipients. A retrospective 12-mo study has been carried out in 14 Spanish centres to assess the efficacy and safety of conversion to EVL in maintenance HT recipients. Two hundred and twenty-two patients were included (mean age: 53 ± 10.5 years; mean time from HT: 8.1 ± 4.5 years). The most common reasons for conversion were nephrotoxicity (30%), chronic allograft vasculopathy (20%) and neoplasms (17%). The doses and mean levels of EVL at baseline (conversion to EVL) and after one year were 1.3 ± 0.3 and 1.2 ± 0.6 mg/d and 6.4 ± 3.4 and 5.6 ± 2.5 ng/mL, respectively. The percentage of patients receiving calcineurin inhibitors (CNIs) at baseline and on the final visit was 95% and 65%, respectively. The doses and mean levels of CNIs decreased between baseline and month 12 from 142.2 ± 51.6 to 98.0 ± 39.4 mg/d (P < 0.001) and from 126.1 ± 50.9 to 89.2 ± 47.7 ng/mL (P < 0.001), respectively, for cyclosporine, and from 2.9 ± 1.8 to 2.6 ± 1.9 mg/d and from 8.3 ± 4.0 to 6.5 ± 2.7 ng/mL (P = 0.011) for tacrolimus. In the subgroup of patients converted because of nephrotoxicity, creatinine clearance increased from 34.9 ± 10.1 to 40.4 ± 14.4 mL/min (P < 0.001). There were 37 episodes of acute rejection in 24 patients (11%). The most frequent adverse events were oedemas (12%), infections (9%) and gastrointestinal problems (6%). EVL was suspended in 44 patients (20%). Since the database was closed at the end of the study, no further follow-up data is available. Conversion to EVL in maintenance HT recipients allowed minimisation or suspension of the CNIs, with improved kidney function in the patients with nephrotoxicity, after 12 mo.

Natural killer cells play a critical role in cardiac allograft vasculopathy in an interleukin-6--dependent manner.

Approximately 50% of cardiac transplants fail in the long term, and currently, there are no specific treatments to prevent chronic rejection. In the clinic, donor cardiac graft ischemia time is limited to within a few hours and correlates with delayed graft function and organ failure. It is still unknown how ischemic injury negatively influences allograft function over the long term despite advances in immunosuppression therapy. Allogeneic cardiac grafts were stored at 4 °C for 4 hr before being transplanted into T/B cell-deficient Rag(-/-) mice or T/B/natural killer (NK) cell-deficient γc(-/-)Rag(-/-) mice. Grafts were harvested 60 days after transplantation and indicators of chronic allograft vasculopathy (CAV) were quantified. We have found that cold ischemia of cardiac grafts induces CAV after transplantation into Rag1(-/-) mice. Interestingly, cold ischemia-induced CAV posttransplantation was not seen in T/B/NK cell-deficient γc(-/-)Rag(-/-) mice. However, cardiac grafts in γc(-/-)Rag(-/-) mice that received an adoptive transfer of NK cells developed CAV, supporting the role of NK cells in CAV development. Analysis of various cytokines that contribute to NK cell function revealed high interleukin (IL)-6 expression in cardiac grafts with CAV. In addition, IL-6-deficient cardiac grafts did not develop CAV after transplantation into allogeneic Rag(-/-) mice. These data demonstrate that cold ischemia and NK cells play critical roles in the development CAV. Natural killer cells and injured grafts may play a reciprocal role for CAV development in an IL-6-independent manner. Specific therapeutic strategies may be required to attenuate NK cell contribution to chronic cardiac rejection.

OR39: UTILITY OF ASSESSING THE C1Q BINDING ABILITY OF HLA ANTIBODIES IN MAXIMIZING DONOR POOLS AND PREDICTING RISK OF TRANSPLANT-RELATED MORBIDITY IN HEART TRANSPLANT

Pre-transplant (txp) sensitization in patients awaiting heart transplants put them at an increased risk post-txp of mortality, rejection, and chronic allograft vasculopathy and also reduces the pool of available donors. Many of the deleterious effects of the HLA antibodies (abs) are associated with their ability to activate the complement cascade. Recent reports have highlighted the correlation between C1q-binding donor-specific HLA abs (DSA) and the increased incidence of antibody-mediated rejection (AMR) and graft loss. It has been suggested that pre-txp identification of DSA that bind C1q will allow for better prediction of the suitability of a potential donor. We present a case report of a broadly sensitized heart txp patient (cPRA = 88%; MFI cutoff = 3,000). Based on the patient’s critical condition and to maximize opportunities for receiving suitable donor offer, MFI levels for unacceptable antigens were raised to 6,000 and a prospective flow cytometric crossmatch requirement was instituted. A low positive T- and B-cell crossmatch was observed with all sera specimen tested and was likely due to the presence of DSA against B49 and B57 (MFI = 4,000–5,000). Patient underwent intraoperative IVIG/plasmapheresis and the txp surgery proceeded without incident. Three weeks post-txp patient developed biopsy proven (strongly and diffusely C4d+) AMR without any concomitant increase in the titers of the DSA. Retrospective study was initiated to compare of the ability of the detected, pre-txp and post-txp HLA abs to bind C1q using single-HLA-antigen-coated beads. Results indicated that HLA abs observed in the pre-txp specimen did not bind C1q, even in the presence of AHG. Significantly and in sharp contrast, isotype switching was evident in the post-txp specimen. Several HLA abs including the DSA (B49) displayed an increased ability to bind C1q. This study highlights 2 important facets of assessing the relevance of identifying the complement-activating ability of HLA abs. Firstly, it suggests that evaluating the presence/absence of C1q binding HLA abs may provide important information to analyze the suitability of a potential donor. Secondly and in contrast, it suggests that evaluating pre-transplant isotype of potential DSA are of limited efficacy in predicting the AMR-free duration post-txp.

Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection.

Selectin-selectin ligand interactions mediate the initial steps in leukocyte migration, an integral part of immune responses. Fucosyltransferase-VII (FucT-VII), encoded by Fut7, is essential for biosynthesis of selectin ligands. In an established model of cardiac allograft vasculopathy and chronic rejection, Fut7(-/-) recipients exhibited long-term graft survival with minimal vasculopathy compared with WT controls. Graft survival was associated with CD4 T-cell exhaustion in the periphery, characterized by impaired effector cytokine production, defective proliferation, increased expression of inhibitory receptors programmed death-1 (PD-1) and T cell Ig- and mucin-domain-containing molecule-3 (Tim-3), low levels of IL-7Rα on CD4 T cells, and reduced migration of polyfunctional CD4 memory T cells to the allograft. Blocking PD-1 triggered rejection only in Fut7(-/-) recipients, whereas depleting regulatory T cells had no effect in either Fut7(-/-) or WT recipients. Adoptive transfer experiments confirmed that this CD4 T cell-exhausted phenotype is seen primarily in Fut7(-/-) CD4 T cells. These data suggest that impaired leukocyte recruitment is a novel mechanism leading to CD4 T-cell exhaustion. Our experimental system serves as an excellent model to study CD4 T-cell exhaustion as a dominant mechanism of transplant tolerance. Further, targeting FucT-VII may serve as a promising strategy to prevent chronic allograft rejection and promote tolerance.

Immunomodulatory Properties of Thalidomide in the Chronic Allograft Vasculopathy Model: Inhibition of Pro-Inflammatory Cytokines and NFκ-B Activation.

Immunomodulatory Properties of Thalidomide in the Chronic Allograft Vasculopathy Model: Inhibition of Pro-Inflammatory Cytokines and NFκ-B Activation.

Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies.

Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR. Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength. Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06). A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.

B cells mediate chronic allograft rejection independently of antibody production

Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture.

Postoperative Complications Associated With Perioperative Sirolimus Prior to Pediatric Cardiac Retransplantation

Sirolimus has been used in pediatric cardiac transplantation for the past decade for chronic renal dysfunction, recurrent rejection, and/or coronary allograft vasculopathy. There has been concern regarding the effect of sirolimus on wound healing and other postoperative complications. To date, the pediatric literature on its use is limited and has not specifically addressed its use in the perioperative period following repeat cardiac transplantation. We compared the patients in our institution who received sirolimus before repeat cardiac transplantation to those in the same era who did not receive sirolimus. Of the 5 patients in the study group, 5 (100%) developed pleural effusions vs 1 (17%) in the control group (p=0.013). There was no increase in mortality in the sirolimus group, and there were no significant differences in renal dysfunction, serious bacterial infection, rejection, or postoperative length of stay. In this small data set, there was a statistically significant increase in pleural effusions in patients on sirolimus. Further study is needed to develop an appropriate strategy to avoid postoperative complications in this patient population.

Immunosuppressive T-cell antibody induction for heart transplant recipients.

Heart transplantation has become a valuable and well-accepted treatment option for end-stage heart failure. Rejection of the transplanted heart by the recipient's body is a risk to the success of the procedure, and life-long immunosuppression is necessary to avoid this. Clear evidence is required to identify the best, safest and most effective immunosuppressive treatment strategy for heart transplant recipients. To date, there is no consensus on the use of immunosuppressive antibodies against T-cells for induction after heart transplantation. To review the benefits, harms, feasibility and tolerability of immunosuppressive T-cell antibody induction versus placebo, or no antibody induction, or another kind of antibody induction for heart transplant recipients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2012), MEDLINE (Ovid) (1946 to November Week 1 2012), EMBASE (Ovid) (1946 to 2012 Week 45), ISI Web of Science (14 November 2012); we also searched two clinical trial registers and checked reference lists in November 2012. We included all randomised clinical trials (RCTs) assessing immunosuppressive T-cell antibody induction for heart transplant recipients. Within individual trials, we required all participants to receive the same maintenance immunosuppressive therapy. Two authors extracted data independently. RevMan analysis was used for statistical analysis of dichotomous data with risk ratio (RR), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological components were used to assess risks of systematic errors (bias). Trial sequential analysis was used to assess the risks of random errors (play of chance). We assessed mortality, acute rejection, infection, Cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, and hyperlipidaemia. In this review, we included 22 RCTs that investigated the use of T-cell antibody induction, with a total of 1427 heart-transplant recipients. All trials were judged to be at a high risk of bias. Five trials, with a total of 606 participants, compared any kind of T-cell antibody induction versus no antibody induction; four trials, with a total of 576 participants, compared interleukin-2 receptor antagonist (IL-2 RA) versus no induction; one trial, with 30 participants, compared monoclonal antibody (other than IL-2 RA) versus no antibody induction; two trials, with a total of 159 participants, compared IL-2 RA versus monoclonal antibody (other than IL-2 RA) induction; four trials, with a total of 185 participants, compared IL-2 RA versus polyclonal antibody induction; seven trials, with a total of 315 participants, compared monoclonal antibody (other than IL-2 RA) versus polyclonal antibody induction; and four trials, with a total of 162 participants, compared polyclonal antibody induction versus another kind, or dose of polyclonal antibodies.No significant differences were found for any of the comparisons for the outcomes of mortality, infection, CMV infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, or hyperlipidaemia. Acute rejection occurred significantly less frequently when IL-2 RA induction was compared with no induction (93/284 (33%) versus 132/292 (45%); RR 0.73; 95% CI 0.59 to 0.90; I(2) 57%) applying the fixed-effect model. No significant difference was found when the random-effects model was applied (RR 0.73; 95% CI 0.46 to 1.17; I(2) 57%). In addition, acute rejection occurred more often statistically when IL-2 RA induction was compared with polyclonal antibody induction (24/90 (27%) versus 10/95 (11%); RR 2.43; 95% CI 1.01 to 5.86; I(2) 28%). For all of these differences in acute rejection, trial sequential alpha-spending boundaries were not crossed and the required information sizes were not reached when trial sequential analysis was performed, indicating that we cannot exclude random errors.We observed some occasional significant differences in adverse events in some of the comparisons, however definitions of adverse events varied between trials, and numbers of participants and events in these outcomes were too small to allow definitive conclusions to be drawn. This review shows that acute rejection might be reduced by IL-2 RA compared with no induction, and by polyclonal antibody induction compared with IL-2 RA, though trial sequential analyses cannot exclude random errors, and the significance of our observations depended on the statistical model used. Furthermore, this review does not show other clear benefits or harms associated with the use of any kind of T-cell antibody induction compared with no induction, or when one type of T-cell antibody is compared with another type of antibody. The number of trials investigating the use of antibodies against T-cells for induction after heart transplantation is small, and the number of participants and outcomes in these RCTs is limited. Furthermore, the included trials are at a high risk of bias. Hence, more RCTs are needed to assess the benefits and harms of T-cell antibody induction for heart-transplant recipients. Such trials ought to be conducted with low risks of systematic and random error.

Chronic Allograft Vasculopathy Correlates with the Downregulation of Selenium-Binding Protein 1 in Smooth Muscle Cells

Selenium binding protein-1 (SBP-1) has been implicated in intracellular protein trafficking and secretion. In a rhesus monkey kidney transplant model we previously demonstrated that SBP-1 is significantly downregulated in the smooth muscle cells (SMC) of arteries with chronic allograft vasculopathy (CAV). The purposes of this study were multiple: (1) to investigate the expression of SBP-1 in human and murine allografts with chronic vasculopathy; (2) to explore factors that …

Six-Month Feeding of Low-Dose Fish Oil Decreases Vascular Expression of High Mobility Group Box1 and Receptor for Advanced Glycation End-Products in Rat Chronic Allograft Vasculopathy

Chronic allograft vasculopathy (CAV) is a typical feature of chronic rejection of small bowel transplantations (SBTx). Our previous studies revealed that feeding fish oil, a natural source of n-3 polyunsaturated fatty acids (PUFAs), protected against CAV. The underlying mechanism remains to be clarified. The pathway mediated by the receptor for advanced glycation end products (RAGE) and its ligand, high mobility group box-1 (HMGB1), which may contribute to the pathogenesis of CAV, is potentially regulated by n-3 PUFAs. Using a chronic rejection model of rat SBTx, the present study investigated whether amelioration of CAV by fish oil feeding was associated with regulation of the RAGE signaling pathway. Moreover, our previous studies also showed that feeding low-dose fish oil for 3 months had no effect. Since an relatively short duration of treatment might fail to produce a visible response, we fed low-dose fish oil for 190 postoperative days. Male inbred Lewis rats and F344 rats were used to establish a chronic rejection model of SBTx. The recipient rats were administered phosphate-buffered saline or fish oil at a daily dose of 3 mL/kg. All rats survived over 190 postoperative days. The expression of HMGB1 and RAGE increased in CAV-bearing vessels. Feeding low-dose fish oil for 6 months attenuated CAV, and significantly reduced HMGB1 and RAGE expressions, indicating beneficial effects of low-dose fish oil on CAV may occur via down-regulation of the HMGB1-RAGE pathway.

IL21 is a critical regulator of chronic/persistent auto-immune and allo-immune responses (P5162)

Abstract IL21 is critical for T1D development in NOD mice, but its role in sustaining T cell responses against islets during T1D progression remains unexplored. Our studies show that diabetic NOD mice have high levels of serum IL21. We thus hypothesized that IL21 produced by activated CD4 T cells in spontaneously diabetic NOD mice sustains T cell responses to islets. Indeed, IL21 is required for maintaining the function of auto-reactive immune cells during T1D progression as transient therapy with IL21 receptor fusion protein (IL21RFc) was effective in reversing the onset of T1D in NOD mice (n=11) and inducing long-term T1D remission for up to 20 weeks in at least 3 mice. Pancreatic infiltrates of IL21RFc-treated NOD mice contain mostly CD4 T cells that lost surface ICOS expression while containing fewer CD8 T cells, suggesting that IL21RFc inhibited CD4 T cell help to CD8 T cells. In a parallel study, we have shown that IL21 deficient mice were protected from chronic allograft vasculopathy in a MHC class-II mismatched cardiac allograft model. However, IL21 deficient mice acutely rejected fully mismatched cardiac allografts similar to wild type. Thus, we have demonstrated a novel and critical role for IL21 signaling in driving chronic immune responses against auto and allo-antigens. Based on our findings, IL21 has the potential to act as a serum biomarker for early T1D detection and a therapeutic target to abrogate persistent T cell responses in T1D and chronic allograft rejection.

Observational Epidemiological Study To Assess Cardiovascular Risk Factors in Heart Transplant Recipients in Spain (CTC Study): Preliminary Results at 18 Months Post-Transplantation

Purpose To date, there are no specific scales to assess the cardiovascular risk (CVR) of heart transplant (HT) recipients. The Cardiac Transplantation & Cardiovascular risk factors (CTC) study is the first to assess the CVR of HT recipients, and the impact of the different cardiovascular risk factors (CVRF) on the morbidity and mortality of this population. Methods and Materials A 3-year, prospective, multicenter, epidemiological study of adult recipients of a first HT in Spain. Both general population- and HT-specific- CVRF were recorded at month 6 (baseline CVR), 12, 18, 24, 30 and 36 post-HT. The main endpoint was to assess the impact of CVRF on the incidence of chronic allograft vasculopathy (CAV), mortality and re-transplantation at 3 years. A HT-specific CVR scale will be developed based on the data analysis. In this preliminary report we present the epidemiological data at 18 months post-HT. Results 404 patients were included (males: 76.3%; mean age: 54.0±10.7 years). The most common reasons for HT were ischemic cardiopathy (41.2%) and dilated cardiomyopathy (39.9%). At 18 months post-HT the accumulated incidence of CAV, mortality and re-transplantation were 11%, 12,9% and 0%, respectively. The most common CVRF were hypertension (72.8%), hyperhomocysteinemia (63.6%) and left ventricular hypertrophy (48.5%). A significant increase in the body mass index (BMI) and in the systolic/diastolic blood pressure was observed between months 6 and 18 post-HT (from 25.6±4.0 kg/m² to 26.8±4.2 kg/m² [p Conclusions After HT a progressive increase in the BMI, blood pressure and estimated CVR are seen. The 3-year data from the CTC study may define the impact of the different CVRF on the outcomes of HT in Spain.

Scandinavian Heart Transplant Everolimus De Novo Study with Early Calcineurin Inhibitor Avoidance (SCHEDULE)

Purpose Calcineurin inhibitors (CNIs) remain the mainstay of immunosuppression following heart transplantation (HTx) but are associated with significant complications such as nephrotoxicity. We therefore designed a randomized trial to assess whether early introduction of everolimus (Evr) followed by withdrawal of cyclosporine (CsA) would lead to superior renal function and less chronic allograft vasculopathy (CAV) in de novo HTx recipients compared to a standard protocol of CsA-based immunosuppression. Methods and Materials A 12 months’ prospective, multicenter, parallell group, open-labeled study with randomization within 5 days post-HTx to CsA, mycophenolate mofetil (MMF) and corticosteroids (CS) (Group A) or to low dose Evr and reduced dose CsA, MMF and CS, with CsA withdrawal and full-dose Evr after 7-11 weeks (Group B). Results The primary objective was to compare renal function assessed by measured glomerual filtration rate (mGFR) 12 months after HTx. Secondary objectives included differences in progression of CAV assessed by IVUS, renal function evaluated by change of mGFR between weeks 7-11 to month 12, renal function estimated by calculated GFR (cGFR) at each follow-up visit, number of rejections and occurence of treatment failures up to 12 months (graft loss, death, loss to follw-up or discontinuation due to lack of efficacy or toxicity), proteinuria, lipid profile, left ventricular function, safety and tolerability). Altogether 116 patients were recruited and randomized to Group A (n = 59) and Group B (n = 57) with mean (SD) age of 51.5 (12.4) and 51.1 (12.8), respectively, from 1. of December 2009 to 31. of December 2011. The last patient will complete the study in December 2012. Conclusions To be presented at the meeting.

Cardiovascular Events with De Novo Use of Everolimus in Heart Transplant Recipients: 24-Month Analysis of the A2310 Study

Purpose Everolimus (EVR) has demonstrated robust evidence for reducing the incidence of chronic allograft vasculopathy at 12 month (IVUS) and may be beneficial in minimizing the risk of cardiovascular events in heart transplant (HTx) recipients. Methods and Materials A2310, a 24 month (M), open-label, multicenter study, randomized 721 HTx recipients to either EVR 1.5mg (C0 3-8ng/mL; N=282) or EVR 3mg (C0 6-12ng/mL; N=168) + reduced cyclosporine (CsA) or MMF 3g (N=271) + standard CsA; with steroids±induction. Here we report the 24 M results assessing the incidence of cardiovascular events (CVE) per patient by treatment. CVE included events related to graft dysfunction, ischaemic heart disease, cerebrovascular disorders, and arterial embolic and thrombotic events. Results Comparison of events are presented only for EVR 1.5 mg vs MMF groups, since enrollment into the EVR 3.0mg arm was stopped early due to higher mortality. By M24 comparable proportions of patients in both groups experienced any CVE. Analyzing the time course of the CVE, patients in the EVR 1.5mg group experienced significantly less events occurring after the first month post-Tx than those in the MMF group, driven by lower incidences of graft dysfunction, ischaemic heart disease and cerebrovascular disorders ( Table ). When occurrence of CVE during the first and the second study year were analyzed separately, the difference in favor of EVR 1.5mg was more pronounced during the second year of follow-up. Conclusions The lower rates of CVE after the first post-operative month in the EVR 1.5mg group may represent the clinical expression of its antiproliferative effect on the vascular intima. Further research is needed to confirm this hypothesis.

Heart transplantation and mechanical circulatory support - From established treatment to current trends in management of end-stage heart failure

Summary In patients with end-stage heart failure refractory to medical and cardiac resynchronisation therapy, heart transplantation is recognised as the treatment of choice. As compared to medical therapy, heart transplantation is considered to be associated with a survival benefit, to enhance functional capacity and improve quality of life, provided that patients are properly selected in accordance with guidelines. However, a powerful trial to compare heart transplantation with conventional management is still lacking and is unlikely to be performed. Individually tailored anti-rejection regimens, based on the currently used immunosuppressive agents, have produced an excellent survival rate following heart transplantation. Unlike the increase in survival in the early phase after transplantation, the attrition rate over the long term has remained similar in recent decades, largely because of associated complications such as chronic allograft vasculopathy and malignancy, the incidence of which could not be markedly reduced. Since the number of heart transplantations is limited due to the shortage of donor organs, and since, in parallel, the number of patients with end-stage heart failure is constantly increasing, mechanical circulatory support is gaining in importance. The pulsatile devices originally used were associated with a high frequency of adverse events such as bleeding and thromboembolic events, noisiness and patient discomfort, which prevented widespread application. The introduction of continuous-flow pumps which are silent and comfortable, and cause fewer side effects, has revolutionised mechanical circulatory support. Since survival on such devices has significantly improved as compared to the previous era, implant rates have dramatically increased, particularly as an alternative to transplantation. In carefully selected patients the outcome of destination therapy approaches survival rates close to those after heart transplantation.

IL21 is a critical regulator of chronic/persistent but not acute/accelerated auto-immune and allo-immune responses

Event Abstract Back to Event IL21 is a critical regulator of chronic/persistent but not acute/accelerated auto-immune and allo-immune responses Mithun Khattar1*, Wenhao Chen1, 2 and Stanislaw Stepkowski1* 1 University of Toledo, Medical Microbiology & Immunology, United States 2 Baylor College of Medicine, United States IL21 is critical for T1D development in NOD mice, but its role in sustaining T cell responses against islets during T1D progression remains unexplored. Our preliminary studies show that NOD mice produce high levels of serum IL21 during T1D onset. Thus, we hypothesize that IL21 produced by activated CD4 T cells in spontaneously diabetic NOD mice sustains T cell responses to islets. We show that IL21 is required for maintaining the function of auto-reactive immune cells during T1D progression as transient therapy with IL21 receptor fusion protein (IL21RFc) is effective in reversing T1D onset in NOD mice (n=11) and inducing long-term T1D remission for up to 30 weeks. Pancreatic infiltrates of IL21RFc-treated NOD mice contain mostly CD4 T cells, that have lost surface ICOS expression, and few CD8 T cells, suggesting that IL21RFc inhibits CD4 T cell help to CD8 T cells. In a parallel study, we also show that IL21 deficient mice are protected from chronic allograft vasculopathy in a MHC class-II mismatched cardiac allograft model. However, IL21 deficient mice acutely reject fully mismatched cardiac allografts, similar to wild type. Thus, we demonstrate a novel and critical role for IL21 signaling in driving chronic immune responses against auto and allo-antigens. Based on our findings, IL21 has the potential to act as a serum biomarker for early T1D detection and a therapeutic target to abrogate persistent T cell responses in T1D and chronic allograft rejection. We continue to investigate the molecular mechanisms governing IL21 mediated chronic immune responses. Keywords: T-cells, type-1diabetes ., Transplantation Immunology, Immune Tolerance, Cytokines Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Khattar M, Chen W and Stepkowski S (2013). IL21 is a critical regulator of chronic/persistent but not acute/accelerated auto-immune and allo-immune responses. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00097 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 08 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Mithun Khattar, University of Toledo, Medical Microbiology & Immunology, Toledo, OH, 43614, United States, mithunkhattar@gmail.com Prof. Stanislaw Stepkowski, University of Toledo, Medical Microbiology & Immunology, Toledo, OH, 43614, United States, stanislaw.Stepkowski@utoledo.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Mithun Khattar Wenhao Chen Stanislaw Stepkowski Google Mithun Khattar Wenhao Chen Stanislaw Stepkowski Google Scholar Mithun Khattar Wenhao Chen Stanislaw Stepkowski PubMed Mithun Khattar Wenhao Chen Stanislaw Stepkowski Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.