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Cell free DNA rejection

Su Kah Goh, Vijayaragavan Muralidharan, Christopher Christophi, Hongdo Do, Alexander Dobrovic
BACKGROUND: Donor-specific cell-free DNA (dscfDNA) is increasingly being considered as a noninvasive biomarker to monitor graft health and diagnose graft rejection after solid-organ transplantation. However, current approaches used to measure dscfDNA can be costly and/or laborious. A probe-free droplet digital PCR (ddPCR) methodology using small deletion/insertion polymorphisms (DIPs) was developed to circumvent these limitations without compromising the quantification of dscfDNA. This method was called PHABRE-PCR (Primer to Hybridize across an Allelic BREakpoint-PCR)...
January 18, 2017: Clinical Chemistry
Vincenzo Cirigliano, Elena Ordoñez, Laura Rueda, Argyro Syngelaki, Kypros H Nicolaides
OBJECTIVE: To assess the performance of screening for fetal trisomies 21, 18 and 13 by cell-free DNA (cfDNA) analysis of maternal blood using a new method based on paired-end massive parallel shotgun sequencing (MPSS). METHODS: Blind study of 1000 plasma samples (1 mL) obtained from women undergoing screening for trisomies 21, 18 and 13 at 11-13 weeks' gestation. The study included 50 cases with confirmed fetal trisomy 21, 30 with trisomy 18, 10 with trisomy 13 and 910 unaffected pregnancies...
December 15, 2016: Ultrasound in Obstetrics & Gynecology
Shinsuke Oshima, Erik E Karrer, Yuka Kawato, Masashi Maeda, Hidehiko Fukahori, Susumu Tsujimoto, Jun Hirose, Koji Nakamura, Takanori Marui, Fujiko Takamura, Takahisa Noto, Steven J Chapin, Yasutomo Fujii, Margaret Neighbors, Sridhar Viswanathan, Bruce H Devens, Yasuyuki Higashi
BACKGROUND: Blockade of CD28-mediated T cell costimulation by a modified cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig), belatacept, is a clinically effective immunosuppressive therapy for the prevention of renal allograft rejection. Use of belatacept-based calcineurin inhibitor-free immunosuppression, however, has demonstrated an increased frequency of cellular rejection episodes and immunosuppression-related safety issues relative to conventional regimens. Furthermore, belatacept typically requires infusion for its administration chronically, which may present an inconvenience to patients...
December 2016: Transplantation
Marica Grskovic, David J Hiller, Lane A Eubank, John J Sninsky, Cindy Christopherson, John P Collins, Kathryn Thompson, Mindy Song, Yue S Wang, David Ross, Mitchell J Nelles, James P Yee, Judith C Wilber, Maria G Crespo-Leiro, Susan L Scott, Robert N Woodward
The use of circulating cell-free DNA (cfDNA) as a biomarker in transplant recipients offers advantages over invasive tissue biopsy as a quantitative measure for detection of transplant rejection and immunosuppression optimization. However, the fraction of donor-derived cfDNA (dd-cfDNA) in transplant recipient plasma is low and challenging to quantify. Previously reported methods to measure dd-cfDNA require donor and recipient genotyping, which is impractical in clinical settings and adds cost. We developed a targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms to accurately quantify dd-cfDNA in transplant recipients without separate genotyping...
October 7, 2016: Journal of Molecular Diagnostics: JMD
Paul M K Gordon, Aneal Khan, Umair Sajid, Nicholas Chang, Varun Suresh, Leo Dimnik, Ryan E Lamont, Jillian S Parboosingh, Steven R Martin, Richard T Pon, Jene Weatherhead, Shelly Wegener, Debra Isaac, Steven C Greenway
Cell-free DNA (cfDNA) has significant potential in the diagnosis and monitoring of clinical conditions. However, accurately and easily distinguishing the relative proportion of DNA molecules in a mixture derived from two different sources (i.e., donor and recipient tissues after transplantation) is challenging. In human cellular transplantation, there is currently no useable method to detect in vivo engraftment, and blood-based non-invasive tests for allograft rejection in solid organ transplantation are either non-specific or absent...
2016: Frontiers in Cardiovascular Medicine
Bjoern Petersen, Antje Frenzel, Andrea Lucas-Hahn, Doris Herrmann, Petra Hassel, Sabine Klein, Maren Ziegler, Klaus-Gerd Hadeler, Heiner Niemann
BACKGROUND: Xenotransplantation is considered to be a promising solution to the growing demand for suitable donor organs for transplantation. Despite tremendous progress in the generation of pigs with multiple genetic modifications thought to be necessary to overcoming the severe rejection responses after pig-to-non-human primate xenotransplantation, the production of knockout pigs by somatic cell nuclear transfer (SCNT) is still an inefficient process. Producing genetically modified pigs by intracytoplasmic microinjection of porcine zygotes is an alluring alternative...
September 2016: Xenotransplantation
Takahiro Tsuji, Masayoshi Miura, Mitsuru Yanai, Hiroe Itami, Yasushi Ishii, Mayuko Akimoto, Yuichiro Fukasawa
Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) has recently been described in cases with glomerular disease. Only 16 cases of recurrent or de novo PGNMID have been reported in the transplanted kidney. Here we report a case of de novo PGNMID in a renal allograft diagnosed in the early stage by protocol biopsy. A 41-year-old male with end-stage kidney disease caused by focal glomerular sclerosis received a living-related kidney transplant. The post-transplantation course was stable, except for an early episode of acute T cell-mediated rejection...
July 2016: Nephrology
Martina Adamek, Gerhard Opelz, Katrin Klein, Christian Morath, Thuong Hien Tran
BACKGROUND: Timely detection of graft rejection is an important issue in the follow-up care after solid organ transplantation. Until now, biopsy has been considered the "gold standard" in the diagnosis of graft rejection. However, non-invasive tests such as monitoring the levels of cell-free DNA (cfDNA) as a sensitive biomarker for graft integrity have attracted increasing interest. The rationale of this approach is that a rejected organ will lead to a significant release of donor-derived cfDNA, which can be detected in the serum of the transplant recipient...
July 1, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
J Beck, M Oellerich, U Schulz, V Schauerte, L Reinhard, U Fuchs, C Knabbe, A Zittermann, C Olbricht, J F Gummert, M Shipkova, I Birschmann, E Wieland, E Schütz
BACKGROUND: In solid organ transplantation, sensitive real-time biomarkers to assess the graft health are desirable to enable early intervention, for example, to avoid full-blown rejections. During rejection, high amounts of graft-derived cell-free DNA (GcfDNA) are shed into the blood stream. The quantification of this GcfDNA in allotransplantation is considered to fulfill this need, because it can be measured with great precision and at reasonable cost. PATIENTS AND METHODS: Patients from 2 ongoing studies in kidney (KTx) and heart (HTx) transplantation were monitored blinded on a scheduled basis, by means of a published universal droplet digital polymerase chain reaction to quantify the GcfDNA...
October 2015: Transplantation Proceedings
Christopher Vollmers, Iwijn De Vlaminck, Hannah A Valantine, Lolita Penland, Helen Luikart, Calvin Strehl, Garrett Cohen, Kiran K Khush, Stephen R Quake
BACKGROUND: It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. METHODS AND FINDINGS: In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire...
October 2015: PLoS Medicine
Iwijn De Vlaminck, Lance Martin, Michael Kertesz, Kapil Patel, Mark Kowarsky, Calvin Strehl, Garrett Cohen, Helen Luikart, Norma F Neff, Jennifer Okamoto, Mark R Nicolls, David Cornfield, David Weill, Hannah Valantine, Kiran K Khush, Stephen R Quake
The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0...
October 27, 2015: Proceedings of the National Academy of Sciences of the United States of America
Michael Oellerich, Philip D Walson, Julia Beck, Jessica Schmitz, Otto Kollmar, Ekkehard Schütz
Although short-term success after solid organ transplantation is good, long-term graft and recipient survival are both not satisfactory. Despite therapeutic drug monitoring (TDM) of immunosuppressive drugs (ISDs), both excessive and insufficient immunosuppression still do occur. There is a need for new biomarkers that, when combined with TDM, can be used to provide more effective and less toxic, personalized immunosuppression to improve long-term survival. Currently used methods are insufficient to rapidly, cost-effectively, and directly interrogate graft integrity after solid organ transplantation...
April 2016: Therapeutic Drug Monitoring
Kevin P Daly
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...
August 2015: Cardiology in the Young
E M Gielis, K J Ledeganck, B Y De Winter, J Del Favero, J-L Bosmans, F H J Claas, D Abramowicz, M Eikmans
After organ transplantation, donor-derived cell-free DNA (ddcfDNA) can be detected in the recipient's blood and urine. Different ddcfDNA quantification techniques have been investigated but a major breakthrough was made with the introduction of digital droplet PCR and massive parallel sequencing creating the opportunity to increase the understanding of ddcfDNA kinetics after transplantation. The observations of increased levels of ddcfDNA during acute rejection and even weeks to months before histologic features of graft rejection point to a possible role of ddcfDNA as an early, noninvasive rejection marker...
October 2015: American Journal of Transplantation
Karin Boer, Kadir Caliskan, Annemiek M A Peeters, Marian C van Groningen, Janneke N Samsom, Alexander P W M Maat, Michiel G H Betjes, Willem Weimar, Carla C Baan
BACKGROUND: FOXP3+ regulatory T cells (Treg) either originate in the thymus (natural [n]Treg) or are induced in the periphery by antigen exposure and cytokines (induced [i]Treg). It is currently not elucidated which and to what extent these Treg subsets regulate intracardiac allogeneic responses in transplant patients. METHODS: By using demethylation of the Treg-specific demethylated region in the FOXP3 gene as a marker for nTreg and FOXP3 messenger RNA expression as a marker for the total Treg population, we examined Treg in endomyocardial biopsies (EMBs) of both patients who developed an acute rejection necessitating therapy (rejectors; International Society for Heart and Lung Transplantation rejection grade ≥ 2R) and patients who remained free from rejection (nonrejectors)...
September 2015: Transplantation
Kevin P Daly
No abstract text is available yet for this article.
March 2015: Annals of Translational Medicine
Hada C Macher, Gonzalo Suárez-Artacho, Juan M Guerrero, Miguel A Gómez-Bravo, Sara Álvarez-Gómez, Carmen Bernal-Bellido, Inmaculada Dominguez-Pascual, Amalia Rubio
BACKGROUND: Health assessment of the transplanted organ is very important due to the relationship of long-term survival of organ transplant recipients and health organ maintenance. Nowadays, the measurement of cell-free DNA from grafts in the circulation of transplant recipients has been considered a potential biomarker of organ rejection or transplant associated complications in an attempt to replace or reduce liver biopsy. However, methods developed to date are expensive and extremely time-consuming...
2014: PloS One
N Poirier, N Dilek, C Mary, S Ville, F Coulon, J Branchereau, X Tillou, V Charpy, S Pengam, V Nerriere-Daguin, J Hervouet, D Minault, S Le Bas-Bernardet, K Renaudin, B Vanhove, G Blancho
Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhibitory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allotransplantation...
January 2015: American Journal of Transplantation
Iwijn De Vlaminck, Hannah A Valantine, Thomas M Snyder, Calvin Strehl, Garrett Cohen, Helen Luikart, Norma F Neff, Jennifer Okamoto, Daniel Bernstein, Dana Weisshaar, Stephen R Quake, Kiran K Khush
Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation...
June 18, 2014: Science Translational Medicine
Damien L Bruno, Devika Ganesamoorthy, Natalie P Thorne, Ling Ling, Melanie Bahlo, Sue Forrest, Marieke Veenendaal, Marina Katerelos, Alison Skene, Frank L Ierino, David A Power, Howard R Slater
BACKGROUND: We describe a novel approach that harnesses the ubiquity of copy number deletion polymorphisms in human genomes to definitively detect and quantify chimeric DNA in clinical samples. Unlike other molecular approaches to chimerism analysis, the copy number deletion (CND) method targets genomic loci (>50 base pairs in length) that are wholly absent from wild-type (i.e., self) background DNA sequences in a sex-independent manner. METHODS: Bespoke quantitative PCR (qPCR) CND assays were developed and validated using a series of DNA standards and chimeric plasma DNA samples collected from 2 allogeneic kidney transplant recipients and 12 pregnant women...
August 2014: Clinical Chemistry
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