Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients.
BACKGROUND
Gene expression profiling distinguishes the absence or presence of moderate to severe grades of acute cellular rejection in cardiac allograft recipients using a 20-gene classifier. We explored the hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations.


METHODS
A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier-derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner.


RESULTS
Mean GE scores not only differentiated Grades >or=3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (p < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and >or=3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades >or=3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade >or=3A rejection, while expression of PDCD1 or SEMA7A showed similar directional patterns without achieving statistical significance.


CONCLUSIONS
These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 1B according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined.
Bernstein
Daniel
D
Department of Pediatrics (Cardiology), Stanford University, Stanford, California 94304, USA. danb@stanford.edu
Williams
Gavin E
GE
Eisen
Howard
H
Mital
Seema
S
Wohlgemuth
Jay G
JG
Klingler
Tod M
TM
Fang
Kenneth C
KC
Deng
Mario C
MC
Kobashigawa
Jon
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics; D001706:Biopsy; D005260:Female; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000145:classification* / Q000175:diagnosis / Q000235:genetics*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor; D039961:Semaphorins / Q000097:blood / Q000235:genetics; D012720:Severity of Illness Index; D044767:Ubiquitin-Protein Ligases / Q000097:blood / Q000235:genetics*
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D058851:GPI-Linked Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C118753:SEMA7A protein, human; D039961:Semaphorins; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases