Transcriptional signals of T-cell and corticosteroid-sensitive genes are associated with future acute cellular rejection in cardiac allografts.
BACKGROUND
Profiling mRNA levels of 11 informative genes expressed by circulating immune effector cells identifies cardiac allograft recipients at low risk for current moderate-severe acute cellular rejection (ACR).


METHODS
We conducted a nested case-control study of 104 cardiac allograft recipients to investigate the association of transcriptional profiles of blood samples with either a future rejection episode within 12 weeks of a baseline clinical sample or persistent histologic quiescence for the same time period.


RESULTS
The transcription profile yielded a score (0 to 40 scale) of 27.4 +/- 6.3 for future rejectors (n = 39) and 23.9 +/- 7.1 for controls (n = 65) (p = 0.01). In patients who were <or=180 days post-transplant, the gene expression score was 28.4 +/- 4.9 for rejectors (n = 28) and 22.4 +/- 7.5 for controls (n = 48) (p < 0.001). In this period, no samples from patients who went on to reject within 12 weeks had gene expression scores of <20. Differential expression of the gene IL1R2 was significantly associated with future events. Of 33 additional genes profiled, 5 supported corticosteroid-sensitive constituents (IL1R2 and FLT3), whereas 6 supported T-cell activation (PDCD1).


CONCLUSIONS
These data suggest that pathways regulating T-cell homeostasis and corticosteroid sensitivity are associated with future ACR in cardiac allografts and suggest that these signals are evident before histologically detectable rejection.
Mehra
Mandeep R
MR
Division of Cardiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. mmehra@medicine.umaryland.edu
Kobashigawa
Jon A
JA
Deng
Mario C
MC
Fang
Kenneth C
KC
Klingler
Tod M
TM
Lal
Preeti G
PG
Rosenberg
Steven
S
Uber
Patricia A
PA
Starling
Randall C
RC
Murali
Srinivas
S
Pauly
Daniel F
DF
Dedrick
Russell
R
Walker
Michael G
MG
Zeevi
Adriana
A
Eisen
Howard J
HJ
D000305:Adrenal Cortex Hormones / Q000502:physiology; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D039481:CD11b Antigen / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000175:diagnosis* / Q000235:genetics*; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009206:Myocardium / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000235:genetics; D053574:Receptors, Interleukin-1 Type II / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000097:blood / Q000235:genetics* / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D039481:CD11b Antigen; C508592:IL1R2 protein, human; C509295:ITGAM protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D053574:Receptors, Interleukin-1 Type II; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3