In renal transplantation, non-invasive biomarkers are needed to identify patients at risk for poor outcomes and guide pre-emptive therapy. Here, we assessed B cell cytokines as a predictive biomarker.

165 patients with serial Bxs (3&12mo protocol+for-cause) and blood draws served as the training set. IS was Thymo→MPA+TAC. Based on prior data, we tested the ratio of IL10:TNFα expression (Cpg+CD40L, by FACs) in peripheral blood T1 transitional B cells (T1B) 3mo post-transplant, as a biomarker. A low T1B IL10:TNFα ratio at 3mo predicted acute rejection (AR) within the 1^st yr (Fig1A). Notably, in patients with a normal Bx at 3mo, a low T1B cytokine ratio strongly predicted late AR (6-12mo;AUC 0.9, p<0.0001). These data were validated in an independent internal cohort (n=74). Further, a low T1B cytokine ratio was associated with IFTA (12 mo) and graft loss/impending graft loss (eGFR<30ml/min & >30% fall from baseline) at 4yrs (Fig1B). The predictive value of this biomarker was not influenced by opportunistic infection or by non-adherence.

Next, T1B cytokine ratio was validated in an external UK cohort (n=100). IS was Simulect→TAC+MMF). All AR in this group was clinical (no protocol Bxs). Again, the T1B cytokine ratio at 3mo strongly predicted AR within the 1^st yr (Fig1C), and was associated with poor graft outcomes (Fig1D).

B cells in high-risk patients express excessive TNFα relative to IL10. Culture of B cells from such patients with α-TNF, reduced TNFα and increased their IL10 expression. Such B cells subsequently suppressed autologous T cell TNFα while increasing IL10 expression. Thus, α-TNF restored a normal B cell cytokine balance (Breg activity) in high-risk patients. Finally, α-TNF inhibited in vitro differentiation of B cells to plasma cells, reduced their Ab secretion and increased their IL-10 expression.

Thus, T1B IL10:TNFα ratio (3mo) was tested and validated as a strong biomarker for subsequent renal allograft rejection and clinical course. Importantly, our data not only identifies patients in need of pre-emptive therapy, but provides rationale for therapeutic intervention based on TNF blockade.

CITATION INFORMATION: Cherukuri A., Chittka D., Sharma A., Salama A., Magee C., Rothstein D. Prospective Multicenter Validation of Human Transitional B Cell Cytokines as a Predictive Biomarker in Renal Transplantation Am J Transplant. 2017;17 (suppl 3).

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