Subclinical T-cell mediated rejection (sc-TCR) accounts for a major cause of kidney allograft loss and is unexpectedly found in a rather important number of protocol biopsies after kidney transplantion. Furthermore, the meaning of specific histological lesions such as borderline changes (BL) are not pathologically well characterized thus, being translated into uncertain clinical interventions in daily clinical practice.

Here, we sought to prospectively immune-monitor the humoral and cellular effector immune responses by means of circulating donor-specific alloantibodies (DSA) by Luminex and donor-specific alloreactive T cells (DSTc) using the IFN-γ ELispot assay in 135 kidney transplant patients, both prior to and at the time of protocol biopsies in order to investigate their dynamics and association to basic histological allograft lesions. An initial discovery set of 45 patients was used to assess the most sensitive and specific IFN-γ Elispot cut-off discriminating sc-TCMR. An independent consecutive cohort of 86 recipients, transplanted between 2011-2013, was used as validation set.

A frequency of 20 IFN-γ-producing DSTc was selected for sc-TCR classification using discriminant analysis (AUC=0.77; 95% CI 0.56-0.95; Sensitivity 75%, Specificity 83%) and validated in the prediction set. Using this cut-off value, 6-mo DSTc were significantly associated to sc-TCR when acute Banff score lesions were classified as IA or higher (13/16 vs 3/16; p=0.003), whereas they were not related to either BL changes (p=NS) or presence of antibody-mediated lesions (p=NS). The prediction of the assay for sc-TCR showed high sensitivity (81.2%) and NPV (93.3%). Interestingly, the absence of circulating DSTc 3 months prior to the protocol biopsy, could also rule out sc-TCR with high accuracy (Sensitivity 80% and NPV=92.3%). Importantly, in the multivariate analysis, DSTc was shown to be an independent correlate predicting sc-TCR (RR=0.115; CI95% 0.018-0.731; p=0.022).

Anti-donor cellular immunity seems to represent a continuum alloimmune process taking place after kidney transplantation in some patients, yielding to specific allograft lesions.

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