*Purpose: Donor specific anti-HLA antibodies (DSA) are a major risk factor associated with renal allograft outcome. As a trigger of B cell antibody production, T follicular helper cells (Tfh) promote DSA appearance. Recent data suggest that cTfh may be present long before DSA appearance.

*Methods: We measured circulating Tfh (cTfh) levels the day of transplantation and one year after in blood from a prospective cohort of 237 renal transplanted patients without DSA during the first year post-transplantation. Total cTfh were characterized as CD4⁺CD45RA^–CXCR5⁺ and three subsets of activated cTfh were analyzed: CXCR5⁺PD1⁺, CXCR5⁺PD1⁺ICOS⁺ and CXCR5⁺PD1⁺CXCR3^–.

*Results: Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5⁺PD1⁺, CXCR5⁺PD1⁺ICOS⁺ and CXCR5⁺PD1⁺CXCR3^– cTfh subsets. Whereas ATG-depleting induction and calcineurin inhibitors treatments decreased the total level of cTfh, activated cTfh subsets were increased at one year post-transplantation. In multivariate survival analysis, we reported on the decrease of activated CXCR5⁺PD1⁺ICOS⁺ at one year after transplantation from blood of DSA-free patients and a significant association with the risk to develop dnDSA after the first year (p=0.018, HR =0.39), independently of HLA mismatches (p=0.003, HR =3.79).

*Conclusions: These results highlight the importance to monitor activated Tfh in patients early after transplantation. They show that current treatments are not able to prevent early enough and efficiently activation and migration of such Tfh, pointing on the need to develop innovative treatments to specifically target them in order to prevent DSA appearance in renal transplantation.

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