Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients.
The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Medicine, Division of Nephrology and Transplant Immunology and phallora@ualberta.ca.
Philip F
PF
Halloran
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada;
Jessica
J
Chang
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada;
Konrad
K
Famulski
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada;
Luis G
LG
Hidalgo
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada;
Israel D R
ID
Salazar
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada;
Maribel
M
Merino Lopez
Department of Surgery, University of Minnesota, Minneapolis, Minnesota;
Arthur
A
Matas
Department of Renal Medicine, Manchester Royal Infirmary, Manchester, United Kingdom;
Michael
M
Picton
Department of Renal Medicine, Manchester Royal Infirmary, Manchester, United Kingdom; Department of Renal Medicine, Beaumont Hospital, Dublin, Ireland;
Declan
D
de Freitas
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland;
Jonathan
J
Bromberg
Servei de Nefrologia, Hospital Vall d'Hebron, Barcelona, Spain; and.
Daniel
D
Serón
Servei de Nefrologia, Hospital Vall d'Hebron, Barcelona, Spain; and.
Joana
J
Sellarés
Department of Nephrology, Medical School of Hannover, Hannover, Germany.
Gunilla
G
Einecke
Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada;
Jeff
J
Reeve
D000906:Antibodies / Q000276:immunology*; D001707:Biopsy, Needle; D016009:Chi-Square Distribution; D015331:Cohort Studies; D005060:Europe; D005260:Female; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000379:methods / Q000401:mortality; D008297:Male; D025202:Molecular Diagnostic Techniques; D009656:North America; D011379:Prognosis; D011507:Proteinuria / Q000175:diagnosis / Q000453:epidemiology; D012189:Retrospective Studies; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D066027:Transplant Recipients / Q000706:statistics & numerical data; D023001:Transplantation Tolerance / Q000276:immunology
D000906:Antibodies
T cells; antibody; graft rejection; kidney transplant; microarrays