Tolerance associated gene expression following allogeneic hematopoietic cell transplantation.

Joseph Pidala,Minnie Sarwal,Steven Eschrich,Claudio Anasetti,Brian C Betts,Francisca Beato,Steve Enkemann,Sean Yoder,Gregory C Bloom,Vassiliki A Boussiotis

doi:10.1371/journal.pone.0117001

Joseph Pidala, Minnie Sarwal + Show 8 more

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https://doi.org/10.1371/journal.pone.0117001

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Abstract

Biologic markers of immune tolerance may facilitate tailoring of immune suppression duration after allogeneic hematopoietic cell transplantation (HCT). In a cross-sectional study, peripheral blood samples were obtained from tolerant (n = 15, median 38.5 months post-HCT) and non-tolerant (n = 17, median 39.5 post-HCT) HCT recipients and healthy control subjects (n = 10) for analysis of immune cell subsets and differential gene expression. There were no significant differences in immune subsets across groups. We identified 281 probe sets unique to the tolerant (TOL) group and 122 for non-tolerant (non-TOL). These were enriched for process networks including NK cell cytotoxicity, antigen presentation, lymphocyte proliferation, and cell cycle and apoptosis. Differential gene expression was enriched for CD56, CD66, and CD14 human lineage-specific gene expression. Differential expression of 20 probe sets between groups was sufficient to develop a classifier with > 90% accuracy, correctly classifying 14/15 TOL cases and 15/17 non-TOL cases. These data suggest that differential gene expression can be utilized to accurately classify tolerant patients following HCT. Prospective investigation of immune tolerance biologic markers is warranted.

Highlights

Biologic markers of immune tolerance may facilitate individualized management of immune suppression following transplantation
The principle finding from our analysis is that differential gene expression in peripheral blood mononuclear cells (PBMC) can provide insight into transplantation tolerance biology, and can be utilized to develop a genomic classifier with a high degree of accuracy to distinguish TOL from non-TOL patients after hematopoietic cell transplantation (HCT)
The Ig receptor superfamily member FCRL3 was over-expressed in the TOL group; this molecule is involved in immune regulation, negatively regulates B cell receptor signaling,[22] and may distinguish a distinct subset of Treg.[23]

Summary

Introduction

Biologic markers of immune tolerance may facilitate individualized management of immune suppression following transplantation. While experimental evidence supports multiple active cellular and molecular mediators of immune tolerance,[1] less data exists in the human clinical setting following solid organ or allogeneic hematopoietic cell transplantation (HCT). Clinical transplantation tolerance has been characterized by absence of ongoing immunologic injury due to incompatibility between donor and recipient without ongoing immunosuppressive (IS) therapy. Acute and chronic graft vs host disease (GVHD), the major clinical manifestations of immunologic injury after HCT, commonly develop or reoccur after attempted IS discontinuation and result in morbidity and mortality.

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