Dataset Information

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.

SUBMITTER: Halloran PF

PROVIDER: S-EPMC4483591 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Halloran Philip F PF Chang Jessica J Famulski Konrad K Hidalgo Luis G LG Salazar Israel D R ID Merino Lopez Maribel M Matas Arthur A Picton Michael M de Freitas Declan D Bromberg Jonathan J Serón Daniel D Sellarés Joana J Einecke Gunilla G Reeve Jeff J

Journal of the American Society of Nephrology : JASN 20141106 7

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 Euro ...[more]

PMID: 25377077

Similar Datasets

Project description:BackgroundCorrelation between antibody-mediated rejection (ABMR) and circulating HLA donor-specific antibodies (HLA-DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of undetected HLA-DSA or non-HLA antibodies contributing to ABMR. Detailed evaluation of the degree of HLA matching together with the identification of non-HLA antibodies in KT may help to decipher the antibody involved.MethodsWe retrospectively assessed patients with transplant biopsies scored following Banff'15 classification. Pre- and post-transplant serum samples were checked for HLA and non-HLA antibodies [MICA-Ab, angiotensin-II type-1-receptor (AT1R)-Ab, endothelin-1 type-A-receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)]. We also analyzed HLA epitope mismatches (HLA-EM) between donors and recipients to explore their role in ABMR histology (ABMRh) with and without HLA-DSA.ResultsOne-hundred eighteen patients with normal histology (n = 19), ABMRh (n = 52) or IFTA (n = 47) were studied. ABMRh patients were HLA-DSApos (n = 38, 73%) or HLA-DSAneg (n = 14, 27%). Pre-transplant HLA-DSA and AT1R-Ab were more frequent in ABMRh compared with IFTA and normal histology cases (p = 0.006 and 0.003), without differences in other non-HLA antibodies. Only three ABMRhDSAneg cases showed non-HLA antibodies. ABMRhDSAneg and ABMRhDSApos cases showed similar biopsy changes and graft-survival. Both total class II and DRB1 HLA-EM were associated with ABMRhDSApos but not with ABMRhDSAneg. Multivariate analysis showed that pre-transplant HLA-DSA (OR: 3.69 [1.31-10.37], p = 0.013) and AT1R-Ab (OR: 5.47 [1.78-16.76], p = 0.003) were independent predictors of ABMRhDSApos.ConclusionsIn conclusion, pre-transplant AT1R-Ab is frequently found in ABMRhDSApos patients. However, AT1R-Ab, MICA-Ab, ETAR-Ab or EC-XM+ are rarely found among ABMRhDSAneg patients. Pre-transplant AT1R-Ab may act synergistically with preformed or de novo HLA-DSA to produce ABMRhDSApos but not ABMRhDSAneg. HLA epitope mismatch associates with ABMRhDSApos compared with ABMRhDSAneg, suggesting factors other than HLA are responsible for the damage.

Project description:BackgroundLate antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy.MethodsWe performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab.ResultsFive (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab.ConclusionsAlthough safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

Project description:Despite major advances in transplant medicine, improvements in long-term kidney allograft survival have not been commensurate with those observed shortly after transplantation. The formation of donor-specific antibodies (DSA) and ongoing antibody-mediated rejection (AMR) processes may critically contribute to late graft loss. However, appropriate treatment for late AMR has not yet been defined. There is accumulating evidence that the proteasome inhibitor bortezomib may substantially affect the function and integrity of alloantibody-secreting plasma cells. The impact of this agent on the course of late AMR has not so far been systematically investigated.The BORTEJECT Study is a randomized controlled trial designed to clarify the impact of intravenous bortezomib on the course of late AMR. In this single-center study (nephrological outpatient service, Medical University Vienna) we plan an initial cross-sectional DSA screening of 1,000 kidney transplant recipients (functioning graft at ?180 days; estimated glomerular filtration rate (eGFR) >20 ml/minute/1.73 m2). DSA-positive recipients will be subjected to kidney allograft biopsy to detect morphological features consistent with AMR. Forty-four patients with biopsy-proven AMR will then be included in a double-blind placebo-controlled intervention trial (1:1 randomization stratified for eGFR and the presence of T-cell-mediated rejection). Patients in the active group will receive two cycles of bortezomib (4?×?1.3 mg/m2 over 2 weeks; 3-month interval between cycles). The primary end point will be the course of eGFR over 24 months (intention-to-treat analysis). The sample size was calculated according to the assumption of a 5 ml/minute/1.73 m2 difference in eGFR slope (per year) between the two groups (alpha: 0.05; power: 0.8). Secondary endpoints will be DSA levels, protein excretion, measured glomerular filtration rate, transplant and patient survival, and the development of acute and chronic morphological lesions in 24-month protocol biopsies.The impact of anti-humoral treatment on the course of late AMR has not yet been systematically investigated. Based on the hypothesis that proteasome inhibition improves the outcome of DSA-positive late AMR, we suggest that our trial has the potential to provide solid evidence towards the treatment of this type of rejection.Clinicaltrials.gov: NCT01873157.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets