Abstract
Intra-renal tertiary lymphoid organs (TLOs) are associated with worsened outcome in kidney transplantation (Ktx). We used an anti-BAFF (B cell activating factor) intervention to investigate whether BAFF is required for TLO formation in a full MHC-mismatch Ktx model in rats. Rats received either therapeutic immunosuppression (no rejection, NR) or subtherapeutic immunosuppression (chronic rejection, CR) and were sacrificed on d56. One group additionally received an anti-BAFF antibody (CR + AB). Intra-renal T (CD3+) and B (CD20+) cells, their proliferation (Ki67+), and IgG+ plasma cells were analyzed by immunofluorescence microscopy. Formation of T and B cell zones and TLOs was assessed. Intra-renal expression of TLO-promoting factors, molecules of T:B crosstalk, and B cell differentiation was analyzed by qPCR. Intra-renal B and T cell zones and TLOs were detected in CR and were associated with elevated intra-renal mRNA expression of TLO-promoting factors, including CXCL13, CCL19, lymphotoxin-β, and BAFF. Intra-renal plasma cells were also elevated in CR. Anti-BAFF treatment significantly decreased intra-renal B cell zones and TLO, as well as intra-renal B cell-derived TLO-promoting factors and B cell differentiation markers. We conclude that BAFF-dependent intra-renal B cells promote TLO formation and advance local adaptive alloimmune responses in chronic rejection.
Highlights
Kidney transplantation is the best available treatment for many patients with end-stage kidney failure; kidney allograft survival is limited, with a 10-year graft survival rate of only 56% [1]
Since T cells were non-significantly reduced in chronic rejection (CR) + AB compared to CR, we assessed the ratio of B:T cells and found that this was elevated in CR compared to NR (0.67 ± 0.29 vs. 0.12 ± 0.16, p = 0.0067), and significantly reduced after anti-BAFF treatment (CR vs. CR + AB: 0.67 ± 0.29 vs. 0.12 ± 0.05, p = 0.0016) (Figure 1D)
We tested if BAFF is required for tertiary lymphoid organs (TLOs) formation in a model of chronic kidney allograft rejection in rats
Summary
Kidney transplantation is the best available treatment for many patients with end-stage kidney failure; kidney allograft survival is limited, with a 10-year graft survival rate of only 56% [1]. Patients with multiple consecutive transplants have a higher risk of graft failure due to rejection [2]. Apart from antibody-mediated rejection (ABMR), which is a major cause of allograft failure [3], kidney allograft inflammation is an important predictor of reduced allograft survival [4]. Subclinical inflammation is associated with poorer outcomes [4,5] and may precede irreversible interstitial fibrosis [6]. The role of B cells in allograft inflammation has not been fully clarified. Intra-graft B cell clusters have been observed in animal and human transplant studies, and have been related to poorer outcomes [7,8]. Overproportional amounts of B cells were found in allografts with subclinical rejection and fibrotic changes compared to grafts with subclinical rejection without fibrosis [9], suggesting a role of B cells in chronic rejection
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