Transitional B cell cytokines predict renal allograft outcomes.

A ratio to predict rejection: Current strategies to identify rejection of transplanted kidneys rely on invasive surveillance biopsies or have limited predictive value. Thus, identification of an early and noninvasive biomarker to predict rejection is required. Here, Cherukuri et al. characterized a ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) expressed by transitional B cells as a biomarker of early T cell–mediated allograft rejection. The authors found that the ratio of IL-10 to TNFα produced by transitional B cells predicted rejection at 3 months after transplantation in three patient cohorts. These findings suggest that the IL-10/TNFα ratio may be an effective biomarker that can be used clinically to tailor therapy based on risk of rejection. Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade. [ABSTRACT FROM AUTHOR]