Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients
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....
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.843452/full |
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| author | Constantin Aschauer Kira Jelencsics Karin Hu Mariella Gregorich Mariella Gregorich Roman Reindl-Schwaighofer Sabine Wenda Thomas Wekerle Andreas Heinzel Rainer Oberbauer |
| author_facet | Constantin Aschauer Kira Jelencsics Karin Hu Mariella Gregorich Mariella Gregorich Roman Reindl-Schwaighofer Sabine Wenda Thomas Wekerle Andreas Heinzel Rainer Oberbauer |
| author_sort | Constantin Aschauer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-24T11:09:41Z |
| format | Article |
| id | doaj.art-483013e7081e426bb1190bd4287d0251 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-24T11:09:41Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-483013e7081e426bb1190bd4287d02512022-12-21T16:58:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-02-011310.3389/fimmu.2022.843452843452Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant RecipientsConstantin Aschauer0Kira Jelencsics1Karin Hu2Mariella Gregorich3Mariella Gregorich4Roman Reindl-Schwaighofer5Sabine Wenda6Thomas Wekerle7Andreas Heinzel8Rainer Oberbauer9Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaSection for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, AustriaDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaDepartment of Blood Group Serology and Transfusion Medicine, Medical University Vienna, Vienna, AustriaDivision of Transplantation, Department of General Surgery, Medical University of Vienna, Vienna, AustriaDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaBackgroundPre-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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.843452/fullkidney transplantationimmune reconstitutionanti-T lymphocyte globulinallorepertoireT-cell receptor (TCR) repertoirelymphocyte depletion therapy |
| spellingShingle | Constantin Aschauer Kira Jelencsics Karin Hu Mariella Gregorich Mariella Gregorich Roman Reindl-Schwaighofer Sabine Wenda Thomas Wekerle Andreas Heinzel Rainer Oberbauer Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients Frontiers in Immunology kidney transplantation immune reconstitution anti-T lymphocyte globulin allorepertoire T-cell receptor (TCR) repertoire lymphocyte depletion therapy |
| title | Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients |
| title_full | Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients |
| title_fullStr | Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients |
| title_full_unstemmed | Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients |
| title_short | Effects of Reduced-Dose Anti-Human T-Lymphocyte Globulin on Overall and Donor-Specific T-Cell Repertoire Reconstitution in Sensitized Kidney Transplant Recipients |
| title_sort | effects of reduced dose anti human t lymphocyte globulin on overall and donor specific t cell repertoire reconstitution in sensitized kidney transplant recipients |
| topic | kidney transplantation immune reconstitution anti-T lymphocyte globulin allorepertoire T-cell receptor (TCR) repertoire lymphocyte depletion therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.843452/full |
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