Impact of preformed T-cell alloreactivity by means of donor-specific and panel of reactive T cells (PRT) ELISPOT in kidney transplantation

PLoS One. 2018 Jul 30;13(7):e0200696. doi: 10.1371/journal.pone.0200696. eCollection 2018.

Abstract

Donor-specific (d-sp) interferon gamma enzyme-linked immunosorbent spot (d-sp ELISPOT) and Panel of reactive T-cell (PRT) ELISPOT assays have been developed to detect alloreactive memory T (Tmem) cells in order to estimate the risk of acute rejection after kidney transplantation. Adding IL15 to the PRT assay (PRT+IL15) may uncover the presence of pathogenic alloreactive CD28-Tmem. Face-to-face comparisons of these assays have not been done yet. We performed pre-transplant d-sp ELISPOT and PRT assays (±IL15, against six B-cell lines) in 168 consecutive kidney transplant recipients and evaluated the multivariable-adjusted associations with biopsy-proven acute rejection (BPAR), de novo donor-specific antibodies (DSA), and eGFR decline over a 48-month follow-up period. D-sp ELISPOT was positive in 81 (48%) subjects, while 71 (42%) and 81 (48%) subjects displayed positive PRT and PRT+IL15, respectively. Their median [interquartile range] numerical test result was 23 [6-65], 18 [8-37], and 26 [10-45] spots/3x105 PBMCs, respectively. The number of PRT spots were weakly correlated with those of d-sp ELISPOT, but highly correlated with PRT+IL15 (rho = 0.96, P<0.001). d-sp ELISPOT, but not PRT (±IL15) was independently associated with BPAR (adjusted Odds Ratio of BPAR associated with d-sp ELISPOT positivity: 4.20 [95%CI: 1.06 to 21.73; P = 0.041]). Unlike d-sp ELISPOT, median PRT and PRT+IL15 were independently associated with higher Δ3-48month eGFR decline post-transplantation (for both assays, about -3mL/min/1.73m2 per one standard deviation unit increase in the spot number). Pre-transplant T-cell immune-monitoring using d-sp ELISPOT and PRT assays identifies kidney transplant candidates at high risk of BPAR and worse kidney allograft progression.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Allografts / immunology
  • Allografts / pathology
  • B-Lymphocytes / immunology
  • Biopsy
  • Enzyme-Linked Immunospot Assay / methods*
  • Female
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Graft Rejection / diagnosis
  • Graft Rejection / epidemiology
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Humans
  • Immunologic Memory / immunology
  • Interferon-gamma / analysis
  • Interferon-gamma / immunology
  • Interleukin-15 / analysis
  • Interleukin-15 / immunology
  • Isoantibodies / immunology
  • Kidney / immunology
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Transplantation / adverse effects*
  • Male
  • Middle Aged
  • Monitoring, Immunologic / methods*
  • Postoperative Period
  • Preoperative Period
  • Prognosis
  • Retrospective Studies
  • T-Lymphocytes / immunology*
  • Tissue Donors

Substances

  • IL15 protein, human
  • Interleukin-15
  • Isoantibodies
  • Interferon-gamma

Grants and funding

This work was partially supported by two Spanish public grants (ISCiii PI16/01321 and ISCiii PI13/01263), a Federer funding, a way to build Europe and a European Commission grant from the Biomarker-Driven Immunosuppression Minimization Consortium (BIODRIM) (No.FP7/2007-2017) to Oriol Bestard. Oriol Bestard received an intensification research grant from the ISCiii (INT15/00112). Sergio Luque received a research fellowship grants from the Catalan Society of Transplantation. Paolo Cravedi, Chiara Donadei and Laura Perin were supported by GOFARR fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.