Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans.
Identifying transplant recipients in whom immunological tolerance is established or is developing would allow an individually tailored approach to their posttransplantation management. In this study, we aimed to develop reliable and reproducible in vitro assays capable of detecting tolerance in renal transplant recipients. Several biomarkers and bioassays were screened on a training set that included 11 operationally tolerant renal transplant recipients, recipient groups following different immunosuppressive regimes, recipients undergoing chronic rejection, and healthy controls. Highly predictive assays were repeated on an independent test set that included 24 tolerant renal transplant recipients. Tolerant patients displayed an expansion of peripheral blood B and NK lymphocytes, fewer activated CD4+ T cells, a lack of donor-specific antibodies, donor-specific hyporesponsiveness of CD4+ T cells, and a high ratio of forkhead box P3 to alpha-1,2-mannosidase gene expression. Microarray analysis further revealed in tolerant recipients a bias toward differential expression of B cell-related genes and their associated molecular pathways. By combining these indices of tolerance as a cross-platform biomarker signature, we were able to identify tolerant recipients in both the training set and the test set. This study provides an immunological profile of the tolerant state that, with further validation, should inform and shape drug-weaning protocols in renal transplant recipients.
Sagoo
Pervinder
P
MRC Centre for Transplantation, King's College London, London, United Kingdom.
Perucha
Esperanza
E
Sawitzki
Birgit
B
Tomiuk
Stefan
S
Stephens
David A
DA
Miqueu
Patrick
P
Chapman
Stephanie
S
Craciun
Ligia
L
Sergeant
Ruhena
R
Brouard
Sophie
S
Rovis
Flavia
F
Jimenez
Elvira
E
Ballow
Amany
A
Giral
Magali
M
Rebollo-Mesa
Irene
I
Le Moine
Alain
A
Braudeau
Cecile
C
Hilton
Rachel
R
Gerstmayer
Bernhard
B
Bourcier
Katarzyna
K
Sharif
Adnan
A
Krajewska
Magdalena
M
Lord
Graham M
GM
Roberts
Ian
I
Goldman
Michel
M
Wood
Kathryn J
KJ
Newell
Kenneth
K
Seyfert-Margolis
Vicki
V
Warrens
Anthony N
AN
Janssen
Uwe
U
Volk
Hans-Dieter
HD
Soulillou
Jean-Paul
JP
Hernandez-Fuentes
Maria P
MP
Lechler
Robert I
RI
D015415:Biomarkers / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology*; D016030:Kidney Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors
D015415:Biomarkers; D007166:Immunosuppressive Agents