Cellular infiltrates and NFκB subunit c-Rel signaling in kidney allografts of patients with clinical operational tolerance

Transplantation. 2012 Oct 15;94(7):729-37. doi: 10.1097/TP.0b013e31826032be.

Abstract

Background: Nuclear factor kappa B (NFκB) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NFκB1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT).

Methods: Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NFκB pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean±SEM.

Results: Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191±81; IR, 291±62; BC, 178±45; and NR, 210±42 cells/mm) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%±1.7%; IR, 3.5%±0.70%; BC, 3.4%±0.57%; and NR, 3.7%±0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2).

Conclusions: Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NFκB pathway and a higher proportion of forkhead box P3-positive cells.

Publication types

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

MeSH terms

  • Adult
  • Biopsy
  • Chi-Square Distribution
  • Female
  • Forkhead Transcription Factors / analysis
  • Graft Rejection / immunology
  • Graft Rejection / metabolism
  • Graft Rejection / pathology
  • Graft Survival
  • HLA-DR Antigens / analysis
  • Humans
  • Immunohistochemistry
  • Immunosuppressive Agents / therapeutic use
  • Kidney / chemistry*
  • Kidney / drug effects
  • Kidney / immunology
  • Kidney / pathology
  • Kidney Transplantation / immunology*
  • Male
  • Middle Aged
  • NF-kappa B p50 Subunit / analysis*
  • Phosphatidylinositol 3-Kinase / analysis
  • Proto-Oncogene Proteins c-akt / analysis
  • Proto-Oncogene Proteins c-rel / analysis*
  • Signal Transduction* / drug effects
  • Time Factors
  • Transplantation Tolerance* / drug effects

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HLA-DR Antigens
  • Immunosuppressive Agents
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • Proto-Oncogene Proteins c-rel
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt