Gene expression profiling distinguishes a molecular signature for grade 1B mild acute cellular rejection in cardiac allograft recipients

J Heart Lung Transplant. 2007 Dec;26(12):1270-80. doi: 10.1016/j.healun.2007.09.017.


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.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Algorithms
  • Antigens, CD / blood
  • Antigens, CD / genetics
  • Apoptosis Regulatory Proteins / blood
  • Apoptosis Regulatory Proteins / genetics
  • Biopsy
  • Female
  • GPI-Linked Proteins
  • Gene Expression Profiling*
  • Graft Rejection / classification*
  • Graft Rejection / diagnosis
  • Graft Rejection / genetics*
  • Heart Transplantation / adverse effects*
  • Humans
  • Male
  • Middle Aged
  • Myocardium / pathology
  • Predictive Value of Tests
  • Prognosis
  • Programmed Cell Death 1 Receptor
  • Semaphorins / blood
  • Semaphorins / genetics
  • Severity of Illness Index
  • Ubiquitin-Protein Ligases / blood
  • Ubiquitin-Protein Ligases / genetics*


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • GPI-Linked Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • SEMA7A protein, human
  • Semaphorins
  • MYLIP protein, human
  • Ubiquitin-Protein Ligases