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

Camila Macedo; Kevin Hadi; John Walters; Beth Elinoff; Marilyn Marrari; Adriana Zeevi; Bala Ramaswami; Geetha Chalasani; Douglas Landsittel; Adele Shields; Rita Alloway; Fadi G Lakkis; E Steve Woodle; Diana Metes

doi:10.1016/j.ekir.2018.11.020

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

Kidney Int Rep. 2018 Dec 8;4(3):455-469. doi: 10.1016/j.ekir.2018.11.020. eCollection 2019 Mar.

Authors

Camila Macedo^{1

2}, Kevin Hadi^{1

2}, John Walters^{1

2}, Beth Elinoff^{1

2}, Marilyn Marrari^{1

3}, Adriana Zeevi^{1

3

4}, Bala Ramaswami^{1

2}, Geetha Chalasani^{1

4

5}, Douglas Landsittel^{1

6}, Adele Shields⁷, Rita Alloway⁸, Fadi G Lakkis^{1

4

5}, E Steve Woodle⁷, Diana Metes^{1

2

4}

Affiliations

¹ Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
² Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³ Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁴ Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁵ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁶ Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁷ Division of Transplantation, University of Cincinnati, Cincinnati, Ohio, USA.
⁸ Division of Nephrology, University of Cincinnati, Cincinnati, Ohio, USA.

Abstract

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.

Keywords: T follicular helper cells; donor-specific anti-HLA antibody; kidney transplantation; thymoglobulin.

Abstract

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