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

American Journal of Transplantation · 2005 · Vol. 6(1) · pp. 150–160

Mario C. Deng✉(University of California, Los Angeles)Howard J. Eisen(University of California, Los Angeles)Mandeep R. Mehra(University of California, Los Angeles)Margaret E. Billingham(University of California, Los Angeles)Charles C. Marboe(University of California, Los Angeles)Gerald J. Berry(University of California, Los Angeles)Jon Kobashigawa(University of California, Los Angeles)F. L. Johnson(University of California, Los Angeles)Randall C. Starling(University of California, Los Angeles)S. Murali(University of California, Los Angeles)Daniel Pauly(University of California, Los Angeles)Helen Baron(University of California, Los Angeles)Jay G. Wohlgemuth(University of California, Los Angeles)R. Woodward(University of California, Los Angeles)Tod M. Klingler(University of California, Los Angeles)Dirk Walther(University of California, Los Angeles)Preeti Lal(University of California, Los Angeles)Steven Rosenberg(University of California, Los Angeles)S. A. Hunt(University of California, Los Angeles)

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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 > or = 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 > or = 3A rejection. Patients >1 year post-transplant with scores below 30 (approximately 68% of the study population) are very unlikely to have grade > or = 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.

Viral Infections and Immunology Research Transplantation: Methods and Outcomes Molecular Biology Techniques and ApplicationsMedicineBiopsyGene expression profilingInternal medicineImmunosuppressionPopulationTransplantationPathologyOncologyGene expression

MeSH terms

AdolescentAdultAgedFemaleGraft RejectionHumansImmunosuppression TherapyLeukocytes, MononuclearMaleMiddle AgedRNA, MessengerHeart TransplantationGene Expression Profiling