Analysis of the Whole CDR3 T Cell Receptor Repertoire after Hematopoietic Stem Cell Transplantation in 2 Clinical Cohorts.

TitleAnalysis of the Whole CDR3 T Cell Receptor Repertoire after Hematopoietic Stem Cell Transplantation in 2 Clinical Cohorts.
Publication TypeJournal Article
Year of Publication2020
AuthorsShah, O, Tamaresis, JS, Kenyon, LJean, Xu, L, Zheng, P, Gupta, P, Rangarajan, K, Lee, S, Spellman, S, Nikiforow, S, Zehnder, J, Meyer, EH
JournalBiol Blood Marrow Transplant
Volume26
Issue6
Pagination1050-1070
Date Published2020 06
ISSN1523-6536
KeywordsClone Cells, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Receptors, Antigen, T-Cell, T-Lymphocytes
Abstract

A major cause of morbidity and mortality for patients who undergo hematologic stem cell transplantation (HSCT) is acute graft-versus-host disease (aGVHD), a mostly T cell-mediated disease. Examination of the T cell receptor (TCR) repertoire of HSCT recipients and the use of next-generation nucleotide sequencing have raised the question of whether features of TCR repertoire reconstitution might reproducibly associate with aGVHD. We hypothesized that the peripheral blood TCR repertoire of patients with steroid-nonresponsive aGVHD would be less diverse. We also hypothesized that patients with GVHD who shared HLA might also share common clones at the time of GVHD diagnosis, thereby potentially providing potential clinical indicators for treatment stratification. We further hypothesized that HSCT recipients with the same HLA mismatch might share a more similar TCR repertoire based on a potentially shared focus of alloreactive responses. We studied 2 separate patient cohorts and 2 separate platforms for measuring TCR repertoire. The first cohort of patients was from a multicenter Phase III randomized double-blinded clinical trial of patients who developed aGVHD (NCT01002742). The second cohort comprised samples from biobanks from 2 transplantation centers and the Center for International Blood and Marrow Transplant Research of patients who underwent mismatched HSCT. There were no statistically significant differences in the TCR diversity of steroid responders and nonresponders among patients with aGVHD on the day of diagnosis. Most clones in the repertoire were unique to each patient, but a small number of clones were found to be both exclusive to and shared among aGVHD nonresponders. We were also able to show a strong correlation between the presence of Vβ20 and Vβ29 and steroid responsiveness. Using the Bhattacharya coefficient, those patients who shared the same HLA mismatch were shown to be no more similar to one another than to those who had a completely different mismatch. Using 2 separate clinical cohorts and 2 separate platforms for analyzing the TCR repertoire, we have shown that the sampled human TCR repertoire is largely unique to each patient but contains glimmers of common clones of subsets of clones based on responsiveness to steroids in aGVHD on the day of diagnosis. These studies are informative for future strategies to assess for reproducible TCR responses in human alloreactivity and possible markers of GVHD responsiveness to therapy.

DOI10.1016/j.bbmt.2020.01.020
Alternate JournalBiol Blood Marrow Transplant
PubMed ID32081787
PubMed Central IDPMC7503214
Grant ListU10 HL069294 / HL / NHLBI NIH HHS / United States
K08 HL119590 / HL / NHLBI NIH HHS / United States
P01 CA049605 / CA / NCI NIH HHS / United States
U24 CA076518 / CA / NCI NIH HHS / United States
U24 HL138660 / HL / NHLBI NIH HHS / United States