Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection

Abstract

Prognostic biomarkers of T cell-mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA-DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P < .0001) including a subset who never developed de novo donor-specific antibodies (P = .002). HLA-DR/DQ molecular mismatch alloimmune risk categories were multivariate correlates of Banff Borderline and Banff ≥ IA TCMR and correlated with the severity and frequency of rejection episodes. Recipient age, HLA-DR/DQ molecular mismatch category, and cyclosporin vs tacrolimus immunosuppression were independent correlates of Banff Borderline and Banff ≥ IA TCMR. In the subset treated with tacrolimus (720/803) recipient age, HLA-DR/DQ molecular mismatch category, and tacrolimus coefficient of variation were independent correlates of TCMR. The correlation of HLA-DR/DQ molecular mismatch category with TCMR, including Borderline, provides evidence for their alloimmune basis. HLA-DR/DQ molecular mismatch may represent a precise prognostic biomarker that can be applied to tailor immunosuppression or design clinical trials based on individual patient risk.

Keywords: T cell-mediated rejection (TCMR); clinical research / practice; graft survival; histocompatibility; immunosuppression / immune modulation; kidney transplantation / nephrology; major histocompatibility complex (MHC); risk assessment / risk stratification.

FIGURE 1

Allograft survival by most severe T cell–mediated rejection (TCMR) phenotype. Recipients with Banff Borderline and Banff ≥ IA T cell–mediated rejection had significantly reduced death‐censored allograft survival (A). After exclusion of recipients who developed de novo donor‐specific antibodies posttransplant, recipients (n = 708) with Banff Borderline and Banff ≥ IA T cell‐mediated rejection had significantly reduced death‐censored allograft survival (B)

FIGURE 2

Banff Borderline, Banff ≥ IA, Banff ≥ IB T cell–mediated rejection (TCMR) free survival by alloimmune risk category. Low, intermediate, or high HLA‐DR/DQ alloimmune risk categories correlated with Banff Borderline, Banff ≥ IA, and Banff ≥ IB T cell–mediated rejection free survival posttransplant

FIGURE 3

De novo DSA free survival by T cell–mediated rejection (TCMR) phenotype. De novo donor‐specific antibody (dnDSA) development posttransplant correlated with T cell–mediated rejection. Recipients who developed dnDSA without preceding or concurrent TCMR (including biopsy at the time of dnDSA development) and then developed their first TCMR episode post‐dnDSA onset were excluded from analysis (n = 4)