Impact of Induction Therapy on Circulating T Follicular Helper Cells and Subsequent Donor-Specific Antibody Formation After Kidney Transplant

Introduction: The cellular events that contribute to generation of donor-specific anti-HLA antibodies (DSA) post- kidney transplantation (KTx) are not well understood. Characterization of such mechanisms could allow tailoring of immunosuppression to benefit sensitized patients. Methods: We prospectively monitored circulating T follicular helper (cT(FH)) cells in KTx recipients who received T-cell depleting (thymoglobulin, n = 54) or T-cell nondepleting (basiliximab, n = 20) induction therapy from pre-KTx to 1 year post- KTx and assessed their phenotypic changes due to induction and DSA occurrence, in addition to healthy controls (n = 13), for a total of 307 blood samples. Results: Before KTx, patients displayed comparable levels of resting, central memory cT(FH) cells with similar polarization to those of healthy controls. Unlike basiliximab induction, thymoglobulin induction significantly depleted cT(FH) cells, triggered lymphopenia-induced proliferation that skewed cT(FH) cells toward increased Th1 polarization, effector memory, and elevated programmed cell death protein 1 (PD-1)(int/hi) expression, resembling activated phenotypes. Regardless of induction, patients who developed DSA post-KTx, harbored pre-KTx donor-reactive memory interleukin (IL)-21(+) cT(FH) cells and showed higher % cT(FH) and lower % of T regulatory (T-REG) cells post-KTx resulting in elevated cT(FH):T-REG ratio at DSA occurrence. Conclusion: Induction therapy distinctly shapes cT(FH) cell phenotype post-KTx. Monitoring cT(FH) cells before and after KTx may help detect those patients prone to DSA generation post-KTx.