Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients

Abstract

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.

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

“…However, histologic results overdiagnosed TCMR in ABMR because ABMR produces TCMR-like v and t lesions as previously reported (4,15). Thus, many mixed biopsies were molecularly pure ABMR.…”

“…The assessment of HLA antibody data has been described (4) and was based on standard of care for the center at the time of biopsy and thus varied between centers and within centers over time. Therefore, HLA antibody assessment reflected contemporary practice at the time of biopsy, which was the intent of the study.…”

“…The biopsy assessment has been detailed elsewhere (4,10,12). Biopsies were processed for histologic examination (periodic acid-Schiff, hematoxylin and eosin, and trichrome) and tested for DSA as per local standard of care.…”

Morphological Structure of Late Renal Graft Dysfunction and Its Effect for Long-Term Results

“…Так, по данным Halloran с соавторами, использование новых диагностических методик позволило диагностировать отторжение лишь на 4% чаще, чем при использовании традици-онных критериев (32% против 28% соответственно). Это происходило прежде всего за счет увеличения доли гуморального и смешанного вариантов, кото-рая составила 20% от всех биопсий [20]. В других исследованиях последних лет частота гуморально-го отторжения также не превышала 20% [21], что может отчасти объясняться тенденцией к усилению ИСТ, отмечающейся после публикации данных ис-следования DeKAF.…”

“…Действительно, в работе Halloran с соавторами было продемонстрировано снижение частоты кле-точного отторжения по мере увеличения сроков после АТП, с полным его исчезновением в отдален-ном (более 10 лет) посттрансплантационном пери-оде [20].…”