Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients.

Thomas Wekerle,Kira Jelencsics,Roman Reindl-Schwaighofer,Mariella Gregorich,Constantin Aschauer,Andreas Heinzel,Karin Hu,Sabine Wenda,Rainer Oberbauer

doi:10.3389/fimmu.2022.843452

Thomas Wekerle, Kira Jelencsics + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2022.843452

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Abstract

BackgroundPre-sensitized kidney transplant recipients have a higher risk for rejection following kidney transplantation and therefore receive lymphodepletional induction therapy with anti-human T-lymphocyte globulin (ATLG) whereas non-sensitized patients are induced in many centers with basiliximab. The time course of lymphocyte reconstitution with regard to the overall and donor-reactive T-cell receptor (TCR) specificity remains elusive.Methods/DesignFive kidney transplant recipients receiving a 1.5-mg/kg ATLG induction therapy over 7 days and five patients with 2 × 20 mg basiliximab induction therapy were longitudinally monitored. Peripheral mononuclear cells were sampled pre-transplant and within 1, 3, and 12 months after transplantation, and their overall and donor-reactive TCRs were determined by next-generation sequencing of the TCR beta CDR3 region. Overall TCR repertoire diversity, turnover, and donor specificity were assessed at all timepoints.ResultsWe observed an increase in the donor-reactive TCR repertoire after transplantation in patients, independent of lymphocyte counts or induction therapy. Donor-reactive CD4 T-cell frequency in the ATLG group increased from 1.14% + -0.63 to 2.03% + -1.09 and from 0.93% + -0.63 to 1.82% + -1.17 in the basiliximab group in the first month. Diversity measurements of the entire T-cell repertoire and repertoire turnover showed no statistical difference between the two induction therapies. The difference in mean clonality between groups was 0.03 and 0.07 pre-transplant in the CD4 and CD8 fractions, respectively, and was not different over time (CD4: F(1.45, 11.6) = 0.64 p = 0.496; CD8: F(3, 24) = 0.60 p = 0.620). The mean difference in R20, a metric for immune dominance, between groups was -0.006 in CD4 and 0.001 in CD8 T-cells and not statistically different between the groups and subsequent timepoints (CD4: F(3, 24) = 0.85 p = 0.479; CD8: F(1.19, 9.52) = 0.79 p = 0.418).ConclusionReduced-dose ATLG induction therapy led to an initial lymphodepletion followed by an increase in the percentage of donor-reactive T-cells after transplantation similar to basiliximab induction therapy. Furthermore, reduced-dose ATLG did not change the overall TCR repertoire in terms of a narrowed or skewed TCR repertoire after immune reconstitution, comparable to non-depletional induction therapy.

Highlights

Pre-sensitized kidney transplant recipients have a higher risk for rejection following kidney transplantation and receive lymphodepletional induction therapy with anti-human T-lymphocyte globulin (ATLG) whereas non-sensitized patients are induced in many centers with basiliximab
The lymphopenic state in our cohort lasted for at least 14 days, and lymphocyte numbers recovered to >1 G/L in two patients at day 310 and three subjects presented with prolonged reduced lymphocyte counts throughout the observation period
Graft function determined by estimated glomerular filtration rate at 12 months after transplantation was not different between the groups (ATLG group: 64 +- 18 ml/min/1.73 m2, basiliximab group: 53 +- 12 ml/min/1.73 m2; p = 0.23)

Summary

Introduction

Pre-sensitized kidney transplant recipients have a higher risk for rejection following kidney transplantation and receive lymphodepletional induction therapy with anti-human T-lymphocyte globulin (ATLG) whereas non-sensitized patients are induced in many centers with basiliximab. Highly immunized individuals are at a higher risk for alloimmunity, and medical immunosuppression is increased to eradicate preexisting donor-reactive lymphocytes and reduce donor-specific antihuman leukocyte antigen (HLA) antibodies (DSAs) in these recipients [1–3]. Patients at risk receive a lymphodepletional induction therapy in most transplant centers such as rabbit anti-human T-lymphocyte globulin (ATLG) or another lymphodepletional agent combined with plasma exchange or immunoadsorption [3]. Dosing for ATLG is heterogeneous in clinical practice as high dosing leads to a profound long-lasting lymphopenia with functional impaired immune cells following reconstitution and increases the incidence of infections and cancer [4, 5]. ATLG provides multifaceted immunomodulation, including T-cell depletion in blood and peripheral lymphoid tissues, induction of apoptosis in B-cell lineages, interference with dendritic cell functional properties, induction of regulatory Tcells and NKT cells, and skewed immune repertoire and impaired T-cell function after reconstitution [9–11]

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