Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression

Phillip A HORWITZ; Emily J TSAI; Mariell L JESSUP; Jonathan A EPSTEIN; Thomas P CAPPOLA; Mary E PUTT; Joan M GILMORE; John J LEPORE; Michael S PARMACEK; Andrew C KAO; Shashank S DESAI; Lee R GOLDBERG; Susan C BROZENA

doi:10.1161/01.CIR.0000150539.72783.BF

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Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression

Journal article

Open access

Peer reviewed

Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression

Phillip A HORWITZ, Emily J TSAI, Mariell L JESSUP, Jonathan A EPSTEIN, Thomas P CAPPOLA, Mary E PUTT, Joan M GILMORE, John J LEPORE, Michael S PARMACEK, Andrew C KAO, …

Circulation (New York, N.Y.), Vol.110(25), pp.3815-3821

2004

DOI: 10.1161/01.CIR.0000150539.72783.BF

PMID: 15583081

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Abstract

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.

Cardiology. Vascular system

General and cellular metabolism. Vitamins

Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous

Blood. Blood coagulation. Reticuloendothelial system

Pharmacology. Drug treatments

Biological and medical sciences

Medical sciences

Blood and lymphatic vessels

Details

Title: Subtitle: Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression
Creators: Phillip A HORWITZ - Department of Internal Medicine, Division of Cardiovascular Diseases, University of Iowa-Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, United States
Emily J TSAI - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Mariell L JESSUP - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Jonathan A EPSTEIN - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Thomas P CAPPOLA - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Mary E PUTT - Division of Biostatistics, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pa., United States
Joan M GILMORE - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
John J LEPORE - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Michael S PARMACEK - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Andrew C KAO - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Shashank S DESAI - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Lee R GOLDBERG - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Susan C BROZENA - Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, United States
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.110(25), pp.3815-3821
DOI: 10.1161/01.CIR.0000150539.72783.BF
PMID: 15583081
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Language: English
Date published: 2004
Academic Unit: Cardiovascular Medicine; Internal Medicine
Record Identifier: 9984094621602771

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