Abstract
The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.
Highlights
Kidney allograft rejection is the major cause for loss of graft function and may have a negative impact on long-term allograft survival
Different morphologies have been described for renal allograft rejection
We characterized different B-cell expression patterns (Figure 1A–E) in 67 randomly selected human biopsies with T cell-mediated rejection (TCMR) and graded them as B-cell rich infiltrates if more than 30 CD20+ cells were detected per high power field (HPF) (Figure 1E)
Summary
Kidney allograft rejection is the major cause for loss of graft function and may have a negative impact on long-term allograft survival. The majority (about 90%) of acute rejections, especially in the first year after ktx, are T cell-mediated [3]. Besides B-cell attraction CXCL13 activates different intracellular pathways that are involved in cell survival, invasion and growth and is able to stimulate resident kidney cells to produce pro-inflammatory cytokines and chemokines [7,9,10,11]. These biological functions of CXCL13 have led us to hypothesize that CXCL13 may be linked to B-cell accumulation in kidney allografts in the presence of TCMR. Our data indicate that CXCL13 blood levels can function as a readily available biomarker for B-cell involvement in T cell-mediated rejection and possibly as a therapeutic target
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