*Purpose: Donor-specific antibodies (DSA) are an increasingly recognized cause of allograft injury, yet biomarkers to predict their development or guide their clinical management post-transplant are not available. CXCL13, the ligand for CXCR5, is a lymphocyte chemoattractant produced within secondary lymphoid organs necessary for germinal center (GC) responses and subsequent antibody formation. GC T follicular helper (Tfh) cells also produce CXCL13, and perturbations in CXCL13 levels have been associated with humoral immune activity. Therefore, it is possible that CXCL13 levels correlate with GC alloreactivity and the formation of DSA following transplantation.

*Methods: We examined serum of human transplant recipients for CXCL13. Healthy human Tfh:B cell co-culture experiments were performed to assess for the ability of cognate Tfh:B cell interactions to produce CXCL13 while generating class-switched antibody responses. A full mismatch BALB/c to B6 murine skin graft model was also utilized to establish the kinetics of serum CXCL13 levels after transplant. ELISAs were used to measure serum CXCL13 levels and PCR was performed for CXCL13 mRNA expression in Tfh:B cell co-culture assays. Flow cytometry was performed of serum crossmatches for the detection of anti-donor antibodies in transplanted mice.

*Results: PCR of Tfh:B cell co-culture experiments indicated that Tfh:memory B cell interactions that led to IgG formation had significantly increased mRNA expression of CXCL13 compared to Tfh:naïve B cell interactions (2.68 fold increase). In skin-grafted mice, serum CXCL13 correlated with alloreactive Tfh and GC B cell responses and preceded the detection of DSA (Figure 1). Serum CXCL13 concentrations in human transplant recipients with DSA (mean, 134 pg/mL) were greater than in healthy controls (48.7 pg/mL) and stable transplant patients without DSA (57.8 pg/mL). In a small number of transplant patients serially observed over the course of DSA formation, serum CXCL13 levels correlated with the development of de novo alloantibodies, peaking prior to the height of HLA antibody detection and contracting to baseline once HLA antibodies plateaued (Figure 2.) Preliminary analysis of serum from kidney transplant recipients biopsied for graft dysfunction showed that CXCL13 was elevated in patients with DSA relative to those without DSA independent of biopsy confirmed rejection.

*Conclusions: CXCL13 indicates GC alloreactivity and alloantibody formation, and correlates with DSA formation in human transplant recipients. As such, CXCL13 has the potential to function as a biomarker for DSA formation and subsequent antibody induced organ injury.

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