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Endomyocardial biopsies with different acute rejection gradings

ABSTRACT: Our goals were to determine whether (i) gene expression patterns in biopsies grouped by acute rejection grade (AR) would be consistent; (ii) a characteristic gene expression profile would be associated with ISHLT Grade 0, 1A & 1B (equivalent to 1R on recently revised criteria) and ISHLT grade 3A & 3B (equivalent to 2R & 3R on recently revised criteria); (iii) gene expression patterns emerging from the analysis would provide insights into mechanisms of AR. The samples used for gene expression profiling were endomyocardial biopsies (EMB) with different acute rejection gradings. The EMB (n=2726) were obtained from the right site of the interventricular septum of heart transplant recipients (n=2423) and graded according to the guidelines of the International Society for Heart and Lung Transplantation (ISHLT, grade 0, n=9; grade1A, n=5; 1B, n=5; 3A, n=4; 3B, n=43). Selection criteria for inclusion of patients in this analysis required the availability of appropriately stored EMB samples for RNA extraction; absence of any infection that required treatment with an antimicrobial drug at anytime during the posttransplant course of the patient; absence of prior AR rejection of any grade; absence of hemodynamic compromise at the time of EMB; use of standard immunosuppressive regimen; and the absence of HLA antibodies prior to transplant.

ORGANISM(S): Homo sapiens

PROVIDER: GSE9377 | GEO | 2008/10/18

SECONDARY ACCESSION(S): PRJNA103085

REPOSITORIES: GEO

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Project description:BACKGROUND: Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. METHODS AND RESULTS: We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). CONCLUSIONS: These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB. Experiment Overall Design: Case- control study with three groups. Patients with rejection (r1-r7), follow-up samples after treatment of rejection (post1-7), and controls with no rejection (con1-7)

Project description:BACKGROUND: Assessment of gene expression in peripheral blood may provide a noninvasive screening test for allograft rejection. We hypothesized that changes in peripheral blood expression profiles would correlate with biopsy-proven rejection and would resolve after treatment of rejection episodes. METHODS AND RESULTS: We performed a case-control study nested within a cohort of 189 cardiac transplant patients who had blood samples obtained during endomyocardial biopsy (EMB). Using Affymetrix HU133A microarrays, we analyzed whole-blood expression profiles from 3 groups: (1) control samples with negative EMB (n=7); (2) samples obtained during rejection (at least International Society for Heart and Lung Transplantation grade 3A; n=7); and (3) samples obtained after rejection, after treatment and normalization of the EMB (n=7). We identified 91 transcripts differentially expressed in rejection compared with control (false discovery rate <0.10). In postrejection samples, 98% of transcripts returned toward control levels, displaying an intermediate expression profile for patients with treated rejection (P<0.0001). Cluster analysis of the 40 transcripts with >25% change in expression levels during rejection demonstrated good discrimination between control and rejection samples and verified the intermediate expression profile of postrejection samples. Quantitative real-time polymerase chain reaction confirmed significant differential expression for the predictive markers CFLAR and SOD2 (UniGene ID No. 355724 and No. 384944). CONCLUSIONS: These data demonstrate that peripheral blood expression profiles correlate with biopsy-proven allograft rejection. Intermediate expression profiles of treated rejection suggest persistent immune activation despite normalization of the EMB. If validated in larger studies, expression profiling may prove to be a more sensitive screening test for allograft rejection than EMB. Keywords: human, peripheral blood, before and after therpay, untreated control

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Endomyocardial biopsies with different acute rejection gradings

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