Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation

Pham, Michael; Teuteberg, Jeffrey J.; Kfoury, Abdallah G.; Starling, Randall C.; Deng, Mario C.; Cappola, Thomas P.; Kao, Andrew; Anderson, Allen S.; Cotts, William; Ewald, Gregory A.; Baran, David A.; Bogaev, Roberta C.; Elashoff, Barbara; Baron, Helen; Yee, James; Valantine, Hannah A.

doi:10.1056/nejmoa0912965

Cited by 445 publications

(355 citation statements)

References 19 publications

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“…Clinical trials assessing the different preventive strategies for CMV should incorporate, in addition to CMV infection and disease, allograft function and survival as primary clinical end points. In addition, the inclusion of newer biomarkers for prediction of allograft dysfunction or rejection, such as microRNA (201) or gene-expression profiling (202), in clinical trials would help determine the potential impact of antiviral preventive strategies in reducing allograft loss.…”

Section: Resultsmentioning

confidence: 99%

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Martín-Gandul

Mueller

Pascual

et al. 2015

American Journal of Transplantation

133

103

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Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community-acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction.

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Section: Resultsmentioning

confidence: 99%

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Martín-Gandul

Mueller

Pascual

et al. 2015

American Journal of Transplantation

133

103

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“…This generic change, occurring despite contemporary immunosuppressive regimens, merits further study as it hints at common pro‐inflammatory pathways in these diverse manifestations of ACR. Admittedly, we restricted our analysis to tissular expression of mRNAs and miRs, whereas others studied their serological expression 7, 39. Furthermore, we only compared rejecting and nonrejecting human samples collected during the first year following HTX, the typical “vulnerable phase” for ACR, whereas others addressed miR expression around 1 year after transplantation 7.…”

Section: Discussionmentioning

confidence: 99%

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

Aelst

Summer

et al. 2016

American Journal of Transplantation

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Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR‐21, ‐142‐3p, ‐142‐5p, ‐146a, ‐146b, ‐155, ‐222, ‐223, and ‐494 increased during ACR in humans and mice, whereas miR‐149‐5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune‐related diseases. Interestingly, 33 of 70 transcripts function downstream of IL‐6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR‐155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR‐155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR‐155, and transcripts, in particular those related to the IL‐6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

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“…This has fueled efforts to discover a more reliable gold standard to detect rejection. One example, the AlloMap test (CareDX) is a biochemical serum assay assessing gene expression profiling to detect early cell-mediated rejection in post-transplant patients (23). Unfortunately, several limitations exist, such as a low positive predictive value, the inability to use the test within the first 2 months after transplant and the inability to detect AMR.…”

Section: Rejectionmentioning

confidence: 99%

The future of cardiac transplantation

Koomalsingh¹,

Kobashigawa²

2018

Ann. Cardiothorac. Surg.

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The first human-to-human heart transplant was performed 50 years ago in 1967. Heart transplantation has now entered an era of tremendous growth and innovation. The future of heart transplantation is bright with the advent of newer immunosuppressive medications and strategies that may even result in tolerance.Much of this progress in heart transplant medicine is predicated on a better understanding of acute and chronic rejection pathways through basic science studies. The future will also include personalized medicine where genomics and molecular science will dictate customized treatment for optimal outcomes. The introduction of mechanical circulatory support (MCS) devices has changed the landscape for patients with severe heart failure to stabilize the most ill patient and make them better candidates for heart transplant.As ex vivo preservation takes hold, we may witness an expansion of the donor pool through the use of donation after cardiac death (DCD) donors. In addition, further geographical donor heart sharing through ex vivo preservation may further decrease waitlist mortality by enabling longer distance donor hearts to be allocated for the sickest waitlist patient. It is no doubt an exciting time to be involved in the field of heart transplantation. In this perspective, we will summarize the present state of heart transplantation and discuss various innovations that are being pursued.

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Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation

Cited by 445 publications

References 19 publications

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

The future of cardiac transplantation

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