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JCI Insight. 2016;1(5). pii: e86252. Epub 2016 Apr 21.

Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide.

Author information

1
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington, USA; Department of Medicine, University of Washington, Seattle, Washington, USA.
3
Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington, USA.
4
Clinical Research Division, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington, USA; Department of Pathology, University of Washington, Seattle, Washington, USA.
5
Public Health Sciences Division, FHCRC, Seattle, Washington, USA.

Abstract

Posttransplantation cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD), but its immunologic impact is poorly understood. We assessed lymphocyte reconstitution via flow cytometry (n = 74) and antigen receptor sequencing (n = 35) in recipients of myeloablative, HLA-matched allogeneic BM transplantation using PTCy. Recovering T cells were primarily phenotypically effector memory with lower T cell receptor β (TRB) repertoire diversity than input donor repertoires. Recovering B cells were predominantly naive with immunoglobulin heavy chain locus (IGH) repertoire diversity similar to donors. Numerical T cell reconstitution and TRB diversity were strongly associated with recipient cytomegalovirus seropositivity. Global similarity between input donor and recipient posttransplant repertoires was uniformly low at 1-2 months after transplant but increased over the balance of the first posttransplant year. Blood TRB repertoires at ≥3 months after transplant were often dominated by clones present in the donor blood/marrow memory CD8+ compartment. Limited overlap was observed between the TRB repertoires of T cells infiltrating the skin or gastrointestinal tract versus the blood. Although public TRB sequences associated with herpesvirus- or alloantigen-specific CD8+ T cells were detected in some patients, posttransplant TRB and IGH repertoires were unique to each individual. These data define the immune dynamics occurring after PTCy and establish a benchmark against which immune recovery after other transplantation approaches can be compared.

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