Dataset Information

Predicting Acute Cardiac Allograft Rejection Using Donor and Recipient Gene Expression

ABSTRACT: Acute rejection in cardiac transplant patients is still a contributing factor to limited survival of the implanted heart. Currently there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplantation acute rejection, which would be of great importance for personalizing immunosuppressive treatment. Within the Biomarkers in Transplantation initiative, the predictive biomarker discovery focused on data and samples collected before or during transplantation such as: clinical variables, genes and proteins from the recipient, and genes from the donor. Based on this study, the best predictive biomarker panel contains genes from the recipient whole blood and from donor endomyocardial tissue and has an estimated area under the curve of 0.90. This biomarker panel provides clinically relevant prediction power and may help personalize immunosuppressive treatment and frequency of rejection monitoring. Overall design: This study, approved by the Providence Health Care Research Ethics Board and related Ethics Boards, was carried out under the Biomarkers in Transplantation (BiT) initiative on subjects who received a cardiac transplant at St. Paul’s Hospital, Vancouver, British Columbia, and signed consent forms. A total of 18 subjects, for whom recipient whole blood (collected in average within two week before transplant) and donor heart tissue (collected at time of transplant) was available, were selected for blood and tissue-based biomarker discovery. Seven of the 18 patients developed acute rejection [AR; ISHLT grade ≥2R] within the first six months post-transplant while 11 did not [non-AR].

INSTRUMENT(S): [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array

ORGANISM(S): Homo Sapiens

SUBMITTER: Bruce Maxwell McManus

PROVIDER: GSE33970 | GEO | 2017-09-29

SECONDARY ACCESSION(S): PRJNA150525

REPOSITORIES: GEO

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Publications

Predicting acute cardiac rejection from donor heart and pre-transplant recipient blood gene expression.

Hollander Zsuzsanna Z Chen Virginia V Sidhu Keerat K Lin David D Ng Raymond T RT Balshaw Robert R Cohen-Freue Gabriela V GV Ignaszewski Andrew A Imai Carol C Kaan Annemarie A Tebbutt Scott J SJ Wilson-McManus Janet E JE McMaster Robert W RW Keown Paul A PA McManus Bruce M BM

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20121221 2

<h4>Background</h4>Acute rejection in cardiac transplant patients remains a contributory factor to limited survival of implanted hearts. Currently, there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplant acute cellular rejection. Such a development would be of great value in personalizing immunosuppressive treatment.<h4>Methods</h4>Recipient age, donor age, cold ischemic time, warm ischemic time, panel-reactive antibody, gender ...[more]

PMID: 23265908

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Project description:In transplantation, there is a critical need for non-invasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor specific exosomes into recipient circulation/ bodily fluids, and that the quantitation and profiling of their intra-exosomal cargoes would constitute a novel biomarker platform for monitoring rejection. We tested this hypothesis in a human into mouse xenogeneic islet transplant model, and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, islet transplant exosomes in recipient blood were quantified over long-term follow-up using anti-human leukocyte antigen (HLA) antibody that is only expressed on human islets (p=1.6x10-14). Transplant islet exosomes were purified using anti-HLA antibody conjugated beads and their cargoes contained bona fide islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to significant decrease in transplant islet exosome signal (p=4x10-15), along with distinct changes in its microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet (n=5) and renal (n=5) transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up (up to 5 years; p=0.0001). Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a non-invasive window into the conditional state of the transplant tissue. Overall design: We assessed an in vivo read-out of TISE cargo as compared to its transplanted human islet tissue counterpart. Transplant islet exosomes from two independent experiments were analyzed. Small RNA microarray profiling of islet exosomes and islet graft tissue was performed. Next, we attempted small RNA profiling of R (rejection)-xeno samples, but because of the low TISE levels from a single sample we had to pool transplant islet exosomes from 5 animals for microarray analysis.

Project description:Background:Innate immunity contributes to acute rejection after kidney transplantation. Genetic polymorphisms affecting innate immunity may therefore influence patients' risk of rejection. IL2 -330T > G, IL10 -1082G > A, -819C > T, and -592C > A, and TNF -308G > A are not associated with acute rejection incidence in Caucasian kidney transplant recipients receiving a calcineurin inhibitor, ciclosporin or tacrolimus (TAC). However, other important innate immune genetic polymorphisms have not yet been extensively studied in recipients and donors. In addition, innate immunogenetics have not been investigated in kidney transplant cohorts receiving only TAC as the calcineurin inhibitor. Objective:To investigate the effect of recipient and donor CASP1, CRP, IL1B, IL2, IL6, IL6R, IL10, MYD88, TGFB, TLR2, TLR4, and TNF genetics on acute kidney rejection in the first 2 weeks post-transplant in TAC-treated kidney transplant recipients. Methods:This study included 154 kidney transplant recipients and 81 donors successfully genotyped for 17 polymorphisms in these genes. All recipients were under triple immunosuppressant therapy of TAC, mycophenolate mofetil, and prednisolone. Recipient and donor genotype differences in acute rejection incidence within the first 2 weeks post-transplantation were assessed by logistic regression, adjusting for induction therapy, human leukocyte antigen mismatches, kidney transplant number, living donor, and peak panel-reactive antibody scores. Results:A trend (Cochran-Armitage P = 0.031) of increasing acute rejection incidence was observed from recipient IL6 -6331 T/T (18%) to T/C (25%) to C/C (46%) genotype [C/C versus T/T odds ratio (95% confidence interval) = 6.6 (1.7 to 25.8) (point-wise P = 0.017)]. However, no genotype differences were significant after Bonferroni correction for multiple comparisons. Conclusions:This study did not detect any statistically significant effects of recipient or donor innate immune genetics on acute rejection incidence in the first 2 weeks post-transplantation. However, the sample size was small, and future larger studies or meta-analyses are required to demonstrate conclusively if innate immune genetics such as IL6 influence the risk of acute rejection after kidney transplantation.