Paul Fields

"T-cell Clonal Dynamics Determined by High Resolution TCR-β Sequencing in Recipients of Allogeneic Hematopoietic Cell Transplantation"

Mark Leick, Rachel M Gittelman, Zachariah DeFilipp, Jerome Ritz, Paul A Fields, Erik Yusko, Catherine Sanders, Harlan Robins, Yi-Bin Chen

Delayed reconstitution of the immune system after allogeneic hematopoietic cell transplantation (HCT) is a long-recognized complication. Specifically, loss of T-cell diversity has been implicated in infectious complications, graft-versus-host disease (GVHD), and disease relapse. We performed immunosequencing using the immunoSEQ® Assay (Adaptive Biotechnologies, Seattle, WA) to characterize the TCRβ locus in 99 HCT recipients. We measured repertoire metrics in the donor and at days +15, +30, +50 and +100 post-transplant in the recipient. Transplant donor type included unrelated (n=57) and related (n=42) donors. Conditioning regimen intensity included reduced intensity (n=55) and myeloablative (n=44). Consistent with prior studies, although absolute T-cell numbers recover relatively quickly after transplant, repertoire diversity remains diminished. Restricted diversity was associated with conditioning intensity, use of ATG, and donor type. Increased T-cell clonal expansion at Day +30 compared to the donor sample was associated with the acute GVHD (HR=1.11, p=5x10-5). Even after exclusion of patients who experienced acute GVHD by day +30 (n=12), the association between acute GVHD and clonal expansion persisted (HR=1.098, p=0.041), indicating that clonal expansion preceded the development of acute GVHD. Our results indicate the importance of early post-transplant sampling and highlight T-cell clonal expansion as a potential novel biomarker for GVHD which warrants further study.