Noninvasive Discrimination of Rejection in Cardiac Allograft Recipients Using Gene Expression Profiling

doi:10.1111/j.1600-6143.2005.01175.x

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Wiley InterScience

American Journal of Transplantation

Volume 6 Issue 1, Pages 150 - 160

Published Online: 13 Dec 2005

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Noninvasive Discrimination of Rejection in Cardiac Allograft Recipients Using Gene Expression Profiling

M. C. Deng ^a*, H. J. Eisen ^a*, M. R. Mehra ^a , M. Billingham ^a , C. C. Marboe ^a , G. Berry ^a , J. Kobashigawa ^a , F. L. Johnson ^a , R. C. Starling ^a , S. Murali ^a , D. F. Pauly ^a , H. Baron ^a , J. G. Wohlgemuth ^a , R. N. Woodward ^a , T. M. Klingler ^a , D. Walther ^a , P. G. Lal ^a , S. Rosenberg ^a and S. Hunt ^a for the CARGO Investigators

^a Drexel University College of Medicine, Philadelphia, Pennsylvania, USA (HJE), Columbia University, New York, NY, USA (MCD, CM, HB), University of Maryland, Baltimore, Maryland, USA (MM, FLJ), Stanford University School of Medicine, Stanford, California, USA (MB, GB, SH), University of California at Los Angeles, Los Angeles, California, USA (JK), Cleveland Clinic Foundation, Cleveland, Ohio, USA (RCS), University of Pittsburgh, Pennsylvania, USA (SM), University of Florida, Gainesville, Florida, USA (DP), XDx, Inc., South San Francisco, California, USA (JGW, RNW, TMK, SR, DW, PGL)

*Corresponding authors: H. J. Eisen, Howard.Eisen@DrexelMed.edu; Mario C. Deng, md785@columbia.edu

M. C. Deng and H. J. Eisen contributed equally to this work.

KEYWORDS

Allogeneic • biological markers • gene expression profiling • graft rejection • heart transplantation • immune response genes • immunologic • immunologic monitoring • transplantation

ABSTRACT

Rejection diagnosis by endomyocardial biopsy (EMB) is invasive, expensive and variable. We investigated gene expression profiling of peripheral blood mononuclear cells (PBMC) to discriminate ISHLT grade 0 rejection (quiescence) from moderate/severe rejection (ISHLT ≥3A). Patients were followed prospectively with blood sampling at post-transplant visits. Biopsies were graded by ISHLT criteria locally and by three independent pathologists blinded to clinical data. Known alloimmune pathways and leukocyte microarrays identified 252 candidate genes for which real-time PCR assays were developed. An 11 gene real-time PCR test was derived from a training set (n = 145 samples, 107 patients) using linear discriminant analysis (LDA), converted into a score (0–40), and validated prospectively in an independent set (n = 63 samples, 63 patients). The test distinguished biopsy-defined moderate/severe rejection from quiescence (p = 0.0018) in the validation set, and had agreement of 84% (95% CI 66% C94%) with grade ISHLT ≥3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade ≥3A rejection (NPV = 99.6%). Gene expression testing can detect absence of moderate/severe rejection, thus avoiding biopsy in certain clinical settings. Additional clinical experience is needed to establish the role of molecular testing for clinical event prediction and immunosuppression management.

Received 22 April 2005, revised and accepted for publication 7 October 2005

DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1600-6143.2005.01175.x About DOI