Immunosuppressive drug-free operational immune tolerance in human kidney transplant recipients: Part I. Blood gene expression statistical analysis.
Survival of solid organ grafts depends on life-long immunosuppression, which results in increased rates of infection and malignancy. Induction of tolerance to allografts would represent the optimal solution for controlling both chronic rejection (CR) and side effects of immunosuppression. Although spontaneous "operational tolerance" can occur in human kidney transplantation, the lack of noninvasive peripheral blood biological markers of this rare phenomenon precludes the identification of potentially tolerant patients in whom immunosuppression could be tapered as well as the development of new tolerance inducing strategies. Here, the potential of high throughput microarray technology to decipher complex pathologies allowed us to study the peripheral blood specific gene expression profile and corresponding EASE molecular pathways associated to operational tolerance in a cohort of human kidney graft recipients. In comparison with patients with CR, tolerant patients displayed a set of 343 differentially expressed genes, mainly immune and defense genes, in their peripheral blood mononuclear cells (PBMC), of which 223 were also different from healthy volunteers. Using the expression pattern of these 343 genes, we were able to classify correctly >80% of the patients in a cross-validation experiment and classified correctly all of the samples over time. Collectively, this study identifies a unique PBMC gene signature associated with human operational tolerance in kidney transplantation by a classical statistical microarray analysis and, in the second part, by a nonstatistical analysis.
Braud
Christophe
C
Institut de Transplantation Et de la Recherche en Transplantation (ITERT), INSERM, U643, Nantes, F-44000 France.
Baeten
Dominique
D
Giral
Magali
M
Pallier
Annaïck
A
Ashton-Chess
Joanna
J
Braudeau
Cecile
C
Chevalier
Catherine
C
Lebars
Alice
A
Léger
Jean
J
Moreau
Anne
A
Pechkova
Eugenia
E
Nicolini
Claudio
C
Soulillou
Jean-Paul
JP
Brouard
Sophie
S
D000328:Adult; D000368:Aged; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods