Heart transplantation offers excellent survival benefit to children with end-stage heart failure. With its success, the number of potential recipients continues to exceed the number of available ...donors. Developing strategies to safely increase donor utilisation is crucial to decreasing wait-list mortality. A new paediatric heart allocation policy is set to be implemented with the goal of prioritising the most urgent listed candidates. Owing to excellent outcomes of ABO-incompatible heart transplantation, the sickest infants will soon receive priority for heart offers irrespective of blood group. Allosensitisation poses unique challenges within the paediatric population; ongoing multi-centre studies are poised to refine our understanding of key risk factors and optimal treatment strategies. Biomarkers for acute cellular rejection, such as donor-specific cell-free DNA, and cardiac allograft vasculopathy, such as VEGF-A, may lead to a decreased need for invasive screening. Ultimately, well-designed and executed randomised control trials of post-transplant immunosuppression are required to improve long-term outcomes after paediatric heart transplantation.
Abstract Background Peripheral blood-based gene expression patterns have been investigated as biomarkers to monitor the immune system and rule out rejection after heart transplantation. Recent ...advances in the high-throughput deep sequencing (HTS) technologies provide new leads in transcriptome analysis. Methods By performing Solexa/Illumina's digital gene expression (DGE) profiling, we analyzed gene expression profiles of PBMCs from 6 quiescent (grade 0) and 6 rejection (grade 2R&3R) heart transplant recipients at more than 6 months after transplantation. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out in an independent validation cohort of 47 individuals from three rejection groups (ISHLT, grade 0,1R, 2R&3R). Results Through DGE sequencing and qPCR validation, 10 genes were identified as informative genes for detection of cardiac transplant rejection. A further clustering analysis showed that the 10 genes were not only effective for distinguishing patients with acute cardiac allograft rejection, but also informative for discriminating patients with renal allograft rejection based on both blood and biopsy samples. Moreover, PPI network analysis revealed that the 10 genes were connected to each other within a short interaction distance. Conclusions We proposed a 10-gene signature for heart transplant patients at high-risk of developing severe rejection, which was found to be effective as well in other organ transplant. Moreover, we supposed that these genes function systematically as biomarkers in long-time allograft rejection. Further validation in broad transplant population would be required before the non-invasive biomarkers can be generally utilized to predict the risk of transplant rejection.
T cells play a critical role in acute allograft rejection. TGF-β/Smad3 signaling is a key pathway in regulating T cell development. We report here that Smad3 is a key transcriptional factor of TGF-β ...signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1β, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+ T cells, and F4/80+ macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-γ while enhancing GATA3 and IL-4 expression, resulting in a shift from the Th1 to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed. In conclusion, Smad3 is an immune regulator in T cell-mediated cardiac allograft rejection. Loss of Smad3 results in a shift from Th1 to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-β/Smad3 signaling may be a novel therapy for acute allograft rejection.
Selective inhibition of lymphocyte activation through abrogation of signal 3-cytokine transduction emerges as a new strategy for immunosuppression. This is the first report on the novel Janus kinase ...(JAK)1/3 inhibitors R507 and R545 for prevention of acute allograft rejection.
Pharmacokinetic and in vitro enzyme inhibition assays were performed to characterize the drugs. Heterotopic Brown Norway-Lewis heart transplantations were performed to study acute cardiac allograft rejection, graft survival, suppression of cellular host responsiveness, and antibody production. Therapeutic and subtherapeutic doses of R507 (60 and 15 mg/kg 2 times per day) and R545 (20 and 5 mg/kg 2 times per day) were compared with those of tacrolimus (Tac; 4 and 1 mg/kg once per day).
Plasma levels of R507 and R545 were sustained high for several hours. Cell-based enzyme assays showed selective inhibition of JAK1/3-dependent pathways with 20-fold or greater selectivity over JAK2 and Tyrosine kinase 2 kinases. After heart transplantation, both JAK1/3 inhibitors reduced early mononuclear graft infiltration, even significantly more potent than Tac. Intragraft interferon-γ release was significantly reduced by R507 and R545, and for interleukin-10 suppression, they were even significantly more potent than Tac. Both JAK1/3 inhibitors and Tac were similarly effective in reducing the host Th1 and Th2, but not Th17, responsiveness and similarly prevented donor-specific immunoglobulin M antibody production. Subtherapeutic and therapeutic R507 and R545 doses prolonged the mean graft survival and were similarly effective as 1 and 4 mg/kg Tac, respectively. In combination regimens, however, only R507 showed highly beneficial synergistic drug interactions with Tac.
Both R507 and R545 are potent novel immunosuppressants with favorable pharmacokinetics and high JAK1/3 selectivity, but only R507 synergistically interacts with Tac.
Here we report a case wherein both donor‐specific and third‐party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody‐mediated rejection in ...a patient who had undergone an orthotopic cardiac transplant six years earlier.
This study describes the onset of cardiac failure due to antibody‐mediated rejection following a miscarriage six years post transplantation.
Data from Cardiac Transplant Research Database (CTRD) were analyzed from 1999 to 2006 to examine the effects of different induction strategies at the time of cardiac transplantation. A total of 2090 ...primary heart transplants were categorized by induction with interleukin‐2 receptor blocker (IL‐2RB), antithymocyte globulin (ATG), or no induction (NI). Probabilities for rejection and infection were estimated with parametric time‐related models. Using these models, hazard was calculated for two theoretical patient profiles, one at lower risk for rejection and higher risk of infection (Profile 1) and higher risk for rejection and lower risk of infection (Profile 2). Of the 2090 transplants, 49.8% (1095) did not receive induction, 27.3% (599) received IL‐2RB, and 18.0% (396) received ATG. Profile 1 patients had lower hazard for rejection with IL‐2RB compared to ATG and NI (p < 0.01), but at the cost of increased risk of infection (5.0 vs. 1.8 vs. 1.6, respectively, at four wk, p < 0.01). Profile 2 patients experienced a fivefold decreased hazard for rejection when treated with IL‐2RB compared with ATG and NI (p < 0.01). In patients at high risk of infection, IL‐2RB reduced risk of rejection but at the expense of increased hazard for infection.
Human cytomegalovirus (HCMV) accelerates transplant vascular sclerosis (TVS), a consequence of angiogenesis (AG) and wound repair (WR). While HCMV can be localized to TVS lesions, the low number of ...infected cells suggests a global effect on target tissues. We used microarray analysis followed by real‐time‐polymerase chain reaction (RT‐PCR) in an RCMV‐accelerated TVS rat cardiac transplant model to determine whether CMV activates host WR and AG factors. Dysregulated cellular genes in allografts from RCMV‐infected recipients were compared to those from uninfected recipients and native hearts. We demonstrated that RCMV upregulates the genes involved in WR and AG, which was highest during the critical time of TVS acceleration (21–28 days). Using a standard in vitro AG assay, virus and serum‐free supernatants collected at 48 h postinfection significantly induced endothelial cell (EC) migration, branching and tubule formation compared to supernatants from mock‐infected cells. Supernatants from ultraviolet (UV)‐inactivated RCMV‐infected cells failed to induce AG, indicating that virus replication is required. Upregulation of WR and AG genes occurs during the critical period of CMV‐accelerated TVS. Targeting these genes may prevent this process and improve allograft survival.
Analysis of rat heart allografts from RCMV‐infected recipients demonstrated that RCMV up‐regulates genes involved in wound healing and angiogenesis, and dysregulation of these genes was highest during the time period of TVS acceleration.
The search for an effective non-invasive monitoring technique for cardiac allograft rejection eluded us until the discovery and validation of a commercially available gene-based peripheral blood ...bio-signature signal. The Invasive Monitoring Attenuation through Gene Expression (IMAGE) trial tested the hypothesis of cardiac biopsy minimization using this gene-based panel in stable, low-risk survivors, late after cardiac transplantation and demonstrated non-inferiority of this strategy. We present a clinician's critical perspective on this important effort and outline the key caveats and highlights for the potential way forward in using these results. Furthermore, we contend that it may not be necessary to replace an invasive cardiac biopsy strategy with anything other than better standardized clinical and functional allograft vigilance in low-risk survivors.
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