Prospective Tracking of Donor-Reactive T-Cell Clones in the Circulation and Rejecting Human Kidney Allografts

Aschauer, Constantin; Jelencsics, Kíra; Hu, Karin; Heinzel, Andreas; Gregorich, Mariella; Vetter, Julia; Schaller, Susanne; Winkler, Stephan; Weinberger, Johannes; Pimenov, Lisabeth; Gualdoni, Guido A.; Eder, Michael; Kainz, Alexander; Troescher, Anna Regina; Regele, Heinz; Reindl‐Schwaighofer, Roman; Wekerle, Thomas; Huppa, Johannes B.; Sykes, Megan; Oberbauer, Rainer

doi:10.3389/fimmu.2021.750005

Cited by 21 publications

(24 citation statements)

References 36 publications

(56 reference statements)

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“…The statistical methods used to examine the repertoires with regard to donor-reactive clonotype distribution, diversity, and similarity between repertoires followed the procedure previously described in depth in (23).…”

Section: Methodsmentioning

confidence: 99%

“…Mixed lymphocyte reactions were performed as previously described, reflecting T-cell activation driven mostly by the direct pathway of allorecognition (23,28). Briefly, after thawing of cryopreserved PBMCs collected prior to transplantation, MLRs were performed by plating 2 × 10 5 carboxyfluorescein…”

Section: Mixed Lymphocyte Reactionmentioning

confidence: 99%

“…Recently, we were able to prove the enrichment of these predefined donor-reactive T-cells not only in the circulating TCR repertoire but also in the rejecting kidney allograft, underlining the immunological importance of these cells in non-sensitized kidney transplant recipients (23).…”

Section: Introductionmentioning

confidence: 98%

“…Improvements in next-generation sequencing (NGS) technologies have made it possible to characterize the overall and donor-reactive T-cell repertoire by T-cell receptor (TCR) sequencing of the circulating T-cells (20,21). In addition, it is possible to specifically define the donor-reactive TCR repertoire pre-transplant and to subsequently track the donor-reactive TCRs after transplantation (22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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

Aschauer

Jelencsics

et al. 2022

Front. Immunol.

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Mixed Lymphocyte Reactionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Aschauer

Jelencsics

et al. 2022

Front. Immunol.

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“…These studies clearly distinguished clonal deletion from anergy, a distinction which often cannot be on the basis of in vitro functional assays. Expansion of circulating donor-reactive sequences was detected in conventional kidney Tx recipients and did not appear to correlate with rejection (80,97).…”

Section: Establishment Of An Alloreactive T Cell Clonal Tracking Platform and Application In Normal Donors And Patients Receiving Solid Omentioning

confidence: 96%

High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity

Khosravi‐Maharlooei

Sykes

2021

Front. Immunol.

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Recent advances in high throughput sequencing (HTS) of T cell receptors (TCRs) and in transcriptomic analysis, particularly at the single cell level, have opened the door to a new level of understanding of human immunology and immune-related diseases. In this article, we discuss the use of HTS of TCRs to discern the factors controlling human T cell repertoire development and how this approach can be used in combination with human immune system (HIS) mouse models to understand human repertoire selection in an unprecedented manner. An exceptionally high proportion of human T cells has alloreactive potential, which can best be understood as a consequence of the processes governing thymic selection. High throughput TCR sequencing has allowed assessment of the development, magnitude and nature of the human alloresponse at a new level and has provided a tool for tracking the fate of pre-transplant-defined donor- and host-reactive TCRs following transplantation. New insights into human allograft rejection and tolerance obtained with this method in combination with single cell transcriptional analyses are reviewed here.

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Circulating T cell specific extracellular vesicle profiles in cardiac allograft acute cellular rejection

Korutla,

Hoffman,

Rostami

et al. 2024

American Journal of Transplantation

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Prospective Tracking of Donor-Reactive T-Cell Clones in the Circulation and Rejecting Human Kidney Allografts

Cited by 21 publications

References 36 publications

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

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

High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity

Circulating T cell specific extracellular vesicle profiles in cardiac allograft acute cellular rejection

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