Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1116-1121 ◽  
Author(s):  
Ephraim P. Hochberg ◽  
Antoinette C. Chillemi ◽  
Catherine J. Wu ◽  
Donna Neuberg ◽  
Christine Canning ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Marrow Transplantation ◽  
Cell Receptor ◽  
Adult Patients ◽  
Thymic Function

Following myeloablative therapy, it is unknown to what extent age-dependent thymic involution limits the generation of new T cells with a diverse repertoire. Normal T-cell receptor gene rearrangement in T-cell progenitors results in the generation of T-cell receptor rearrangement excision circles (TRECs). In this study, a quantitative assay for TRECs was used to measure T-cell neogenesis in adult patients with leukemia who received myeloablative therapy followed by transplantation of allogeneic hematopoietic stem cells. Although phenotypically mature T cells had recovered by 1 to 2 months after bone marrow transplantation (BMT), TREC levels remained low for 3 months after BMT. T-cell neogenesis became evident by 6 months, and normal levels of adult thymic function were restored at 6 to 12 months after BMT. Subsequent leukemia relapse in some patients was associated with reduced TREC levels, but infusion of mature donor CD4+ T cells resulted in rapid restoration of thymic function. These studies demonstrate that T-cell neogenesis contributes to immune reconstitution in adult patients and suggest that thymic function can be manipulated in vivo.

scholarly journals Evidence for extrathymic generation of intermediate T cell receptor cells in the liver revealed in thymectomized, irradiated mice subjected to bone marrow transplantation.

1995 ◽  
Vol 182 (3) ◽  
pp. 759-767 ◽  
Author(s):  
K Sato ◽  
K Ohtsuka ◽  
K Hasegawa ◽  
S Yamagiwa ◽  
H Watanabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Marrow Transplantation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Phenotypic Characterization ◽  
Receptor Cells

In addition to the major intrathymic pathway of T cell differentiation, extrathymic pathways of such differentiation have been shown to exist in the liver and intestine. In particular, hepatic T cells of T cell receptors or CD3 of intermediate levels (i.e., intermediate T cell receptor cells) always contain self-reactive clones and sometimes appear at other sites, including the target tissues in autoimmune diseases and the tumor sites in malignancies. To prove their extrathymic origin and self reactivity, in this study we used thymectomized, irradiated (B6 x C3H/He) F1 mice subjected to transplantation of bone marrow cells of B6 mice. It was clearly demonstrated that all T cells generated under athymic conditions in the peripheral immune organs are intermediate CD3 cells. In the case of nonthymectomized irradiated mice, not only intermediate CD3 cells but also high CD3 cells were generated. Phenotypic characterization showed that newly generated intermediate CD3 cells were unique (e.g., interleukin 2 receptor alpha-/beta+ and CD44+ L-selectin-) and were, therefore, distinguishable from thymus-derived T cells. The precursor cells of intermediate CD3 cells in the bone marrow were Thy-1+ CD3-. The extrathymic generation of intermediate CD3 cells was confirmed in other combinations of bone marrow transplantation, C3H --> C3H and B10.Thy1.1 --> B6.Thy1.2. The generated intermediate CD3 cells in the liver contained high levels of self-reactive clones estimated by anti-V beta monoclonal antibodies in conjunction with the endogenous superantigen minor lymphocyte-stimulating system, especially the combination of B6 --> (B6 x C3H/He) (graft-versus-host-situation).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2585-2594 ◽  
Author(s):  
CL Mackall ◽  
L Granger ◽  
MA Sheard ◽  
R Cepeda ◽  
RE Gress
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Cell Receptor ◽  
Cell Regeneration ◽  
Thymic Function ◽  
T Cell Progenitors ◽  
Isoform Expression

Abstract To study the source of regenerated T cells after bone marrow transplantation (BMT), lethally irradiated thymectomized and thymus- bearing C57BL/6 (Thy 1.2+) mice were injected with syngeneic T-cell depleted bone marrow (TCD BM) cells and graded numbers of congenic B6/Thy 1.1+ lymph node (LN) cells. LN cell expansion was the predominant source for T-cell regeneration in thymectomized hosts but was minimal in thymus-bearing hosts. Analysis of T-cell receptor (TCR) expression on LN progeny showed a diverse V beta repertoire. Therefore, peripheral T-cell progenitors exist within V beta families, but expansion of these progenitors after BMT is downregulated in the presence of a functional thymus. CD4+ cells derived from BM versus LN in thymus-bearing hosts displayed differential CD44 and CD45 isoform expression. BM-derived cells were primarily CD45RB+CD44lo and LN derived cells were nearly exclusively CD45RB- CD44hi. In thymectomized hosts, BM, host, and LN CD4+ progeny were CD45RB- CD44hi. We conclude that T-cell regeneration via peripheral T-cell progenitors predominates in hosts lacking thymic function and gives rise to T cells that display a “memory” phenotype. In contrast, the ability to generate sizable populations of “naive” type T cells after BMT appears limited to the prethymic progenitor pool and could serve as a marker for thymic regenerative capacity.

scholarly journals T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2585-2594 ◽  
Author(s):  
CL Mackall ◽  
L Granger ◽  
MA Sheard ◽  
R Cepeda ◽  
RE Gress
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Cell Receptor ◽  
Cell Regeneration ◽  
Thymic Function ◽  
T Cell Progenitors ◽  
Isoform Expression

To study the source of regenerated T cells after bone marrow transplantation (BMT), lethally irradiated thymectomized and thymus- bearing C57BL/6 (Thy 1.2+) mice were injected with syngeneic T-cell depleted bone marrow (TCD BM) cells and graded numbers of congenic B6/Thy 1.1+ lymph node (LN) cells. LN cell expansion was the predominant source for T-cell regeneration in thymectomized hosts but was minimal in thymus-bearing hosts. Analysis of T-cell receptor (TCR) expression on LN progeny showed a diverse V beta repertoire. Therefore, peripheral T-cell progenitors exist within V beta families, but expansion of these progenitors after BMT is downregulated in the presence of a functional thymus. CD4+ cells derived from BM versus LN in thymus-bearing hosts displayed differential CD44 and CD45 isoform expression. BM-derived cells were primarily CD45RB+CD44lo and LN derived cells were nearly exclusively CD45RB- CD44hi. In thymectomized hosts, BM, host, and LN CD4+ progeny were CD45RB- CD44hi. We conclude that T-cell regeneration via peripheral T-cell progenitors predominates in hosts lacking thymic function and gives rise to T cells that display a “memory” phenotype. In contrast, the ability to generate sizable populations of “naive” type T cells after BMT appears limited to the prethymic progenitor pool and could serve as a marker for thymic regenerative capacity.

scholarly journals Different T-cell receptor repertoires between lesions and peripheral blood in acute graft-versus-host disease after allogeneic bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3019-3026 ◽  
Author(s):  
K Kubo ◽  
K Yamanaka ◽  
H Kiyoi ◽  
H Fukutani ◽  
M Ito ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
T Cell Receptor ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Acute Graft

From the viewpoint of T-cell receptor (TCR) repertoire, we studied the role of T cells in acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. By means of inverse polymerase chain reaction method and DNA sequencing, we analyzed TCR-alpha and -beta transcripts from GVHD lesions and peripheral blood (PB) in a patient with typical GVHD together with PB from donor. At the initial onset of GVHD, V alpha-7 and -19 subfamilies were oligoclonally expanded in the PB compared with those in the oral mucosal lesions. At the second onset, V alpha-2, and V beta-6 subfamilies were more frequently detected in the cutaneous lesion than in the PB. Some TCR transcripts were recurrently found either in the mucosal or cutaneous lesions (or in both) and not in the PB. Furthermore, some of recurrent TCR transcripts in the lesions shared V gene segments and common motifs of complementarity determining region-3. These findings suggested that T cells infiltrating the GVHD lesions recognized a limited kind of antigens presented by patient's tissues with GVHD, and that T-cell repertoire in the GVHD lesions was different from that in the PB.

scholarly journals Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology

2003 ◽  
Vol 176 (3) ◽  
pp. 305-311 ◽  
Author(s):  
V Geenen ◽  
JF Poulin ◽  
ML Dion ◽  
H Martens ◽  
E Castermans ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Endocrine Disorders ◽  
Thymic Function ◽  
Excision Circles ◽  
The Impact ◽  
Self Antigens

Although the thymus constitutes a target organ for most protein and steroid hormones, it has been quite difficult to determine the precise control exerted in vivo by the endocrine system upon thymic function. The biological role of the thymus is to ensure the generation of a diversified population of peripheral T cells able to respond to non-self-antigens but nevertheless tolerant to self-antigens. For a long time, thymic function could not be monitored, as a consequence of the absence of adequate technology to differentiate recent thymic emigrants from naive T cells. The generation of T cell receptor (TCR) diversity occurs in the thymus through recombination of gene segments encoding the variable parts of the TCR alpha and beta chains. During these processes, by-products of the rearrangements are generated in the form of TCR excision circles (TRECs). As these molecules are lost upon further cell division, their quantification is actually considered as a very valuable tool to estimate thymic function. The most appropriate TREC is deltaRec-Psi(J)alpha TREC or signal joint TREC resulting from deltaRec-Psi(J)alpha rearrangement (TCRD deletion) that occurs late during thymopoiesis, before V(alpha)-J(alpha) rearrangement. Here we describe how TREC quantification is a powerful and reliable method to evaluate the impact of hormones and endocrine disorders upon thymic function.

scholarly journals A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1280-1287 ◽  
Author(s):  
Thomas Fehr ◽  
Carrie L. Lucas ◽  
Josef Kurtz ◽  
Takashi Onoe ◽  
Guiling Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Tolerance Induction ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
Cd4 Cells

Abstract Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1−/− mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell–intrinsic NFAT1 requirement for CD8 tolerance in vivo.

scholarly journals Stable clonal expansion of T cells induced by bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 789-799 ◽  
Author(s):  
K Masuko ◽  
S Kato ◽  
M Hagihara ◽  
F Tsuchida ◽  
Y Takemoto ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Gene Segment ◽  
Clonal Expansion ◽  
General Tendency ◽  
Beta Gene

The immune mechanisms of T cells regeneration after bone marrow transplantation (BMT) and the factors maintaining allogeneic marrow graft in the host are still unknown. To pursue this issue, we analyzed T-cell clonality of peripheral blood lymphocytes (PBLs) in BMT recipients, using reverse transcription polymerase chain reaction with T-cell receptor (TCR) V beta gene segment-specific primers and single- strand conformation polymorphism. PBLs from patients and donors showed a heterogeneous T-cell population with oligoclonal accumulations of CD8+ T cells. When PBLs were cultured in HLA-matched mixed lymphocytes reaction in vitro, no distinct clonal expansion was observed. However, after BMT, oligoclonal expansions were induced in the recipients in vivo, without a restriction of TCR V beta gene usage. Although part of the expansion was transient, the majority was repeatedly detected even several months later. Our results suggested that certain in vivo mechanisms maintain a stable clonal expansion of distinct T cells in marrow recipients. We also found in a single patient with graft-versus- host disease a replacement of expanded clones by other clones during follow-up. Diminishing numbers of accumulation clones were found in long-term marrow recipients, indicating a general tendency for clonal expansion to subside progressively. Considered together, our data suggest the involvement of clonally expanded T cells in lymphoid regeneration and in acute and chronic immune responses after BMT.

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