Clinical implications and longitudinal alteration of peripheral blood transcriptional signals indicative of future cardiac allograft rejection.

BACKGROUND: We have previously demonstrated that a peripheral blood transcriptional profile using 11 distinct genes predicts onset of cardiac allograft rejection weeks to months prior to the actual event. METHODS: In this analysis, we ascertained the performance of this transcriptional algorithm in a Bayesian representative population: 28 cardiac transplant recipients who progressed to moderate to severe rejection; 53 who progressed to mild rejection; and 46 who remained rejection-free. Furthermore, we characterized longitudinal alterations in the transcriptional gene expression profile before, during and after recovery from rejection. RESULTS: In this patient cohort, we found that a gene expression score (range 0 to 40) of or =3A) rejection; 16 of 53 (30%) from the intermediate group (those who progressed to ISHLT Grade 1B or 2) and 13 of 46 (28%) controls (who remained Grade 0 or 1A) had scores < or =20. A gene score of > or =30 was associated with progression to moderate to severe rejection in 58% of cases. These two extreme scores (< or =20 or > or =30) represented 44% of the cardiac transplant population within 6 months post-transplant. In addition, longitudinal gene expression analysis demonstrated that baseline scores were significantly higher for those who went on to reject, remained high during an episode of rejection, and dropped post-treatment for rejection (p < 0.01). CONCLUSIONS: The use of gene expression profiling early after transplantation allows for separation into low-, intermediate- or high-risk categories for future rejection, permitting development of discrete surveillance strategies.

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

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.