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| Item Type: | Article |
|---|---|
| Title: | Prospective tracking of donor-reactive T-cell clones in the circulation and rejecting human kidney allografts |
| Creators Name: | Aschauer, C., Jelencsics, K., Hu, K., Heinzel, A., Gregorich, M.G., Vetter, J., Schaller, S., Winkler, S.M., Weinberger, J., Pimenov, L., Gualdoni, G.A., Eder, M., Kainz, A., Troescher, A.R., Regele, H., Reindl-Schwaighofer, R., Wekerle, T., Huppa, J.B., Sykes, M. and Oberbauer, R. |
| Abstract: | BACKGROUND: Antigen recognition of allo-peptides and HLA molecules leads to the activation of donor-reactive T-cells following transplantation, potentially causing T-cell-mediated rejection (TCMR). Sequencing of the T-cell receptor (TCR) repertoire can be used to track the donor-reactive repertoire in blood and tissue of patients after kidney transplantation. METHODS/DESIGN: In this prospective cohort study, 117 non-sensitized kidney transplant recipients with anti-CD25 induction were included. Peripheral mononuclear cells (PBMCs) were sampled pre-transplant and at the time of protocol or indication biopsies together with graft tissue. Next-generation sequencing (NGS) of the CDR3 region of the TCRbeta chain was performed after donor stimulation in mixed lymphocyte reactions to define the donor-reactive TCR repertoire. Blood and tissue of six patients experiencing a TCMR and six patients without rejection on protocol biopsies were interrogated for these TCRs. To elucidate common features of T-cell clonotypes, a network analysis of the TCR repertoires was performed. RESULTS: After transplantation, the frequency of circulating donor-reactive CD4 T-cells increased significantly from 0.86 ± 0.40% to 2.06 ± 0.40% of all CD4 cells (p < 0.001, mean dif.: -1.197, CI: -1.802, -0.593). The number of circulating donor-reactive CD4 clonotypes increased from 0.72 ± 0.33% to 1.89 ± 0.33% (p < 0.001, mean dif.: -1.168, CI: -1.724, -0.612). No difference in the percentage of donor-reactive T-cells in the circulation at transplant biopsy was found between subjects experiencing a TCMR and the control group [p = 0.64 (CD4(+)), p = 0.52 (CD8(+))]. Graft-infiltrating T-cells showed an up to six-fold increase of donor-reactive T-cell clonotypes compared to the blood at the same time (3.7 vs. 0.6% and 2.4 vs. 1.5%), but the infiltrating TCR repertoire was not reflected by the composition of the circulating TCR repertoire despite some overlap. Network analysis showed a distinct segregation of the donor-reactive repertoire with higher modularity than the overall TCR repertoire in the blood. These findings indicate an unchoreographed process of diverse T-cell clones directed against numerous non-self antigens found in the allograft. CONCLUSION: Donor-reactive T-cells are enriched in the kidney allograft during a TCMR episode, and dominant tissue clones are also found in the blood. |
| Keywords: | T-Cell Receptor, Alloreactivity, Kidney Transplant, Rejection, Next Generation Sequencing, Network Analysis |
| Source: | Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Publisher: | Frontiers Media SA |
| Volume: | 12 |
| Page Range: | 750005 |
| Date: | 14 October 2021 |
| Official Publication: | https://doi.org/10.3389/fimmu.2021.750005 |
| PubMed: | View item in PubMed |
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