Donor-specific anti-HLA antibodies (DSA) represent an important biomarker for acute rejection and are a major cause of long-term graft failure after kidney transplantation (KTx). The cellular mechanisms that lead to the development of DSA are not entirely understood. Here we analyzed the phenotypic polarization and activation status of CXCR5⁺CD45RO⁺CD4⁺ circulating (c)T follicular helper cell (T_FH), which are known to be involved in antibody production by B cells. We have consented 30 Thymoglobulin-induced KTx patients participating in an ongoing observational cross-sectional study. Nineteen patients were identified as DSA (MFI>1000) carriers, including 8 patients undergoing an acute antibody-mediated rejection (ABMR) and 11 patients with asymptomatic DSA. In addition, 6 patients were considered stable and DSA-, and 5 patients presented with an acute cellular rejection (ACR) only. Whole blood were obtained from patients with asymptomatic DSA or at the time of for cause biopsy and analyzed by flow cytometry to identify cT_FH subsets: Th1 (CXCR3⁺), Th17 (CCR6⁺), Th1/Th17 (CXCR3⁺CCR6⁺) and Th2 (CXCR3^–CCR6^–) as well as the co-expression of activation markers PD1 and ICOS (PD1⁺/ICOS⁺).

Our results showed that although patients who developed DSA had similar levels (%) cT_FH cells as compared to DSA- patients (mean ± STDV 17%±7.4 and 22.5%±10), they presented significantly higher activation markers (PD1⁺/ICOS⁺) on their Th1, Th1/Th17, and Th17 cT_FH subtypes (9%±10.6 and 19.8%±16.4 p=0.05; 3.7%±4 and 17.8%±11 p<0.001; 2.3%±2.3 and 7.3%±5.6 p=0.04). In addition, ABMR KTx patients unlike those with ACR presented higher % cT_FH cells (22.3%±8.6 and 9.7%±5.3; p=0.01) with higher PD1⁺/ICOS⁺ expression (14.2%±10.3 and 4.6%±4.4; p=0.06) which was observed in all 4 cT_FH subsets (Th1, Th2, Th1/17, and Th17).

In conclusion, patients who developed either asymptomatic DSA or ABMR, unlike stable DSA- or ACR patients displayed activated cT_FH cells that may directly provide allo-Ag specific cognate help to B cells for shaping DSA generation after KTx. Monitoring cT_FH cell subsets may uniquely allow the development of novel diagnostic and predictive biomarkers for graft outcomes and tailored therapy in patients with DSA.

CITATION INFORMATION: Macedo C, Fadakar P, Hadi K, Ellinof B, Zeevi A, Hariharan S, Metes D. Activated Th1 and Th17 cT_FH Phenotype Correlates with DSA Production in Kidney Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).

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