Early ReportAssessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution
Introduction
Myeloablative chemotherapy followed by bone-marrow transplantation or peripheral-blood haematopoietic stemcell transplantation is associated with substantial T-cell immunodeficiency.1, 2 Although the thymus is the primary site of T lymphopoiesis during fetal and early postnatal life, its role in reconstitution of the adult immune system after bone-marrow or haematopoietic stem-cell transplantation remains controversial.3, 4, 5, 6 T-cell reconstitution can involve both a thymus-dependent pathway (the generation of new naïve T cells from haematopoietic stem cells), and a thymus-independent pathway (peripheral expansion of pre-existing memory T cells).2, 7 The thymus-dependent pathway has the potential advantage of reconstituting antigen-specific responses which were not present within the mature T cells that routinely accompany bone-marrow and haematopoietic stem-cell grafts. However, studies suggest that the thymus-dependent pathway is age-dependent and becomes severely limited after childhood,2, 3, 4, 5, 6, 8, 9, 10 presumably due to thymic involution. These studies relied on cellsurface molecules, such as isoforms of CD45, to differentiate naïve recent thymic emigrants from memory or effector T cells. However, T cells expressing a naïve phenotype are not necessarily accurate surrogate markers of thymic function. After thymic emigration, CD45RA-positive naïve T cells can have a long, quiescent lifespan11, 12 may proliferate in an antigen-independent manner,13 or may rapidly convert to CD45RO-positive memory or effector T cells.14 Furthermore, naïve T-cell markers may be acquired by memory T cells.15
During thymocyte development, rearrangement of the T-cell-receptor (TCR) gene leads to the excision of circular DNA fragments from genomic DNA.16 We have developed an assay which can be used to estimate thymic output more accurately by measuring the numbers of TCR-rearrangement excision circles (TREC) in peripheral-blood T cells.17 These products are stable, unique to T cells, and are not duplicated during mitosis, which means that they are diluted out with each cellular division.16, 17 Thus TREC are markers of developmental proximity to the thymus, and their concentrations in peripheral blood can be used to estimate thymic output.17 To accomplish this estimation, we used a TREC derived from a unique recombination event which is common to about 70% of thymocytes destined to become mature TCR-αβ T cells.17 We previously reported that although thymic function declines with age, substantial output is maintained into late adulthood. Furthermore, the adult thymus can contribute to immune reconstitution in HIV-infected individuals after treatment with antiretroviral drugs.17
In this study, we aimed to find out whether the adult thymus can make a contribution to immune recovery by quantification of numbers of TREC in the peripheral-blood mononuclear cells of patients with multiple myeloma, who received myeloablative chemotherapy and autologous peripheral-blood haematopoietic stem-cell transplantation with unmanipulated grafts or grafts enriched for CD34-positive haematopoietic stem cells.
Section snippets
Patients
Samples from 40 patients aged 34–66 were available from a group of 134 patients with multiple myeloma enrolled in a multicentre phase III trial.18 The subgroup of patients we studied had received haematopoietic stem-cell transplantation and had stable or responsive disease after a minimum of three chemotherapy cycles. Patients who had disease progression within 1 year of transplantation were excluded. No DNA samples remained available for patients who had undergone immunoglobulin gene analysis,
Patients
19 of the 40 patients received granulocyte-CSF-mobilised peripheral-blood mononuclear cells enriched for CD34-positive haematopoietic stem cells, and 21 received unmanipulated autografts.18 CD34 enrichment, which was used clinically in this case to diminish tumour load, decreases autograft T-cell burden by three log factors, but does not abolish it.22 There were no significant baseline differences between the two groups with respect to age, T-cell counts, numbers of TREC, or previous
Discussion
There is a substantial, and potentially detrimental, period of T-cell immunodeficiency after bone-marrow transplantation and haematopoietic stem-cell transplantation.1, 2 Rapid but transient recovery of limited T-cell immunity is mediated by the expansion of a small population of pre-existing T-cell clones–the thymus-independent pathway.2, 7, 9, 10, 19, 20, 21 However, complete reconstitution of comprehensive immunity with a broad TCR repertoire would require the generation of new naïve T-cells
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