The Kinetics of Early T and B Cell Immune Recovery after Bone Marrow Transplantation in RAG-2-Deficient SCID Patients

Atar Lev,Ninette Amariglio,Gideon Rechavi,Amos J Simon,Raz Somech,Mor Bareket,Daphna Hutt,Bella Bielorai,Andrew J Yates

doi:10.1371/journal.pone.0030494

Abstract

The kinetics of T and B cell immune recovery after bone marrow transplantation (BMT) is affected by many pre- and post-transplant factors. Because of the profoundly depleted baseline T and B cell immunity in recombination activating gene 2 (RAG-2)-deficient severe combined immunodeficiency (SCID) patients, some of these factors are eliminated, and the immune recovery after BMT can then be clearly assessed. This process was followed in ten SCID patients in parallel to their associated transplant-related complications. Early peripheral presence of T and B cells was observed in 8 and 4 patients, respectively. The latter correlated with pre-transplant conditioning therapy. Cells from these patients carried mainly signal joint DNA episomes, indicative of newly derived B and T cells. They were present before the normalization of the T cell receptor (TCR) and the B cell receptor (BCR) repertoire. Early presentation of the ordered TCR gene rearrangements after BMT occurred simultaneously, but this pattern was heterogeneous over time, suggesting different and individual thymic recovery processes. Our findings early after transplant could suggest the long-term patients' clinical outcome. Early peripheral presence of newly produced B and T lymphocytes from their production and maturation sites after BMT suggests donor stem cell origin rather than peripheral expansion, and is indicative of successful outcome. Peripheral detection of TCR excision circles and kappa-deleting recombination excision circles in RAG-2-deficient SCID post-BMT are early markers of T and B cell reconstitution, and can be used to monitor outcome and tailor specific therapy for patients undergoing BMT.

Highlights

Severe combined immunodeficiency (SCID) is characterized by significantly low levels of T and B cells and profound defective immune function
We demonstrated that high proportions of T and B cells containing signal joints appeared early after Bone marrow transplantation (BMT), suggesting cell neogenesis rather than cell proliferation
Morbidity and mortality after transplantation was found in association with low TCR excision circles (TRECs) values [25] and BMT-related complications, such as acute graft versus host disease (GVHD) or its treatment, which had a transient impact on TREC numbers [26]

Summary

Introduction

Severe combined immunodeficiency (SCID) is characterized by significantly low levels of T and B cells and profound defective immune function. The thymus and the bone marrow are the primary anatomic sites for T and B cell neogenesis from undifferentiated hematopoietic progenitor cells. Within these organs, hematopoietic progenitor cells that have been committed to the T and B cell lineage undergo rapid proliferation and differentiation to mature cells. Hematopoietic progenitor cells that have been committed to the T and B cell lineage undergo rapid proliferation and differentiation to mature cells During this process, a diverse receptor repertoire is formed, and the resulting cells are able to respond to a wide array of internally and externally processed antigens [3,4,5]. TREC quantification is extensively used as an accurate measure of thymic function and T cell neogenesis, and this analysis was suggested as a diagnostic tool for T cell immunodeficiency [8], for neonatal screen assay to detect SCID immediately after birth [9], and as TREC TCRD-d/D2-D3 TCRD-d/D2-J1 TCRD-d/V1-J1 TCRA-REC KREC-SJ KREC-CJ

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Conclusion