Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation

Chung, Brile; Barbara-Burnham, Lucia; Barsky, Lora; Weinberg, Kenneth I.

doi:10.1182/blood.v98.5.1601

Cited by 111 publications

(94 citation statements)

References 37 publications

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“…Finally, our data are not consistent with evidence that exogenous IL-7 enhances thymopoiesis in mice after bone marrow transplantation (65,66). It has been demonstrated that the effects of IL-7 in this setting are attributable to radiation-induced damage to IL-7-producing thymic stromal cells resulting in decreased endogenous IL-7 production in transplanted mice (67). Consequently, the use of IL-7 in these models represents IL-7 replacement in the setting of relative IL-7 deficiency, whereas our model involves the use of exogenous IL-7 in animals with presumably intact endogenous IL-7 production.…”

Section: Discussioncontrasting

confidence: 99%

Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

Napolitano

Stoddart

Hanley

et al. 2003

The Journal of Immunology

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IL-7 is a critical component of thymopoiesis in animals and has recently been shown to play an important role in T cell homeostasis. Although there is increasing interest in the use of IL-7 for the treatment of lymphopenia caused by the HIV type 1, evidence that IL-7 may accelerate HIV replication has raised concerns regarding its use in this setting. We sought to identify the effects of IL-7 on human thymocyte survival and to determine the impact of IL-7 administration on in vivo HIV infection of the human thymus. Using in vitro analysis, we show that IL-7 provides potent anti-apoptotic and proliferative signals to early thymocyte progenitors. Analysis of CD34+ subpopulations demonstrates that surface IL-7 receptor is expressed on most CD34highCD5+CD1a− thymocytes and that this subpopulation appears to be one of the earliest maturation stages responsive to the effects of IL-7. Thus, IL-7 provides survival signals to human thymocytes before surface expression of CD1a. CD4+CD8+ thymocytes are relatively unresponsive to IL-7, although IL-7 protects these cells from dexamethasone-induced apoptosis. IL-7 has a predominantly proliferative effect on mature CD4+CD3+CD8− and CD8+CD3+CD4− thymocytes. In contrast to the in vitro findings, we observe that in vivo administration of IL-7 to SCID-hu Thy/Liv mice does not appear to enhance thymocyte survival nor does it appear to accelerate HIV infection. Given the growing interest in the use of IL-7 for the treatment of human immunodeficiency, these findings support additional investigation into its in vivo effects on thymopoiesis and HIV infection.

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Section: Discussioncontrasting

confidence: 99%

Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

Napolitano

Stoddart

Hanley

et al. 2003

The Journal of Immunology

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“…[6][7][8][9][10] Particularly in the hematopoietic stem cell transplantation setting, peripheral expansion of T cells can contribute significantly to the composition of the T cell compartment post HSCT. 11 As additional factors, radiotherapy 12 and graft-versus-host disease (GVHD) [13][14][15][16] post HSCT and thymic involution as a part of ageing have a negative impact on thymic function. 15,17,18 Thymic function has been assessed by imaging and analysis of T cell subtypes in blood but more recently also by measuring TRECs (T cell receptor excision circles).…”

Section: Introductionmentioning

confidence: 99%

T cell regeneration in pediatric allogeneic stem cell transplantation

Olkinuora

Talvensaari

Kaartinen

et al. 2007

Bone Marrow Transplant

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Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P ¼ 0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P ¼ 0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P ¼ 0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.

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“…34 There is also evidence that thymic output can be influenced by donor lymphocyte infusions (DLI) 37 and pre-BMT radiotherapy. 38 The aim of this study was to carry out a comprehensive analysis of T cell subset reconstitution, thymic output and those factors that affect T cell reconstitution post HCT. We have used a combination of the TREC assay, T cell phenotyping and analysis of the TCR Vb repertoire to elucidate the contribution of thymic-dependent and thymicindependent pathways to reconstitution of the T cell compartment and have carried out an analysis of the factors affecting the utilisation of each of these pathways.…”

mentioning

confidence: 99%

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

Fallen

McGreavey

Madrigal

et al. 2003

Bone Marrow Transplant

106

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Summary:The factors affecting T cell reconstitution post haematopoietic cell transplantation (HCT) are not well characterised. We carried out a longitudinal analysis of T cell reconstitution in 32 HCT recipients during the first 12 months post transplant. We analysed reconstitution of naı¨ve, memory and effector T cells, their diversity and monitored thymic output using TCR rearrangement excision circles (TRECs). Thymic-independent pathways were responsible for the rapid reconstitution of memory and effector T cells less than 6 months post HCT. Thymic-dependent pathways were activated between 6 and 12 months in the majority of patients with naı¨ve T cell numbers increasing in parallel with TREC levels. Increasing patient age, chronic GVHD and T cell depletion (with or without pretransplant Campath-1H) predicted low TREC levels and slow naı¨ve T cell recovery. Furthermore, increasing patient age also predicted high memory and effector T cell numbers. The effects of post HCT immunosuppression, total body irradiation, donor leucocyte infusions, T cell dose and post HCT infections on T cell recovery were also analysed. However, no effects of these single variables across a variety of different age, GVHD and T cell depletion groups were apparent. This study suggests that future analysis of the factors affecting T cell reconstitution and studies aimed at reactivating the thymus through therapeutic intervention should be analysed in age-, GVHD-and TCD-matched patient groups. While each of these parameters may have mutually exclusive effects on the outcome of the transplant, it is the combination of all of these parameters that will determine the ultimate success of the transplant. Furthermore, the effects of each of these parameters on immune reconstitution post HCT are unclear.The immediate post transplant period is followed by a severe and often prolonged immune deficiency that results in prolonged susceptibility to infection. 8,17,[19][20][21][22] Although infections that occur in the first month after engraftment probably result from deficiencies in both granulocytes and other mononuclear cell subsets, the more prolonged immune deficiency arises from deficiencies in effective CD4 þ T cell and B cell reconstitution and immunosuppressive therapy. 23,[27][28][29] It was then suggested that the reconstitution and maintenance of effective T cell immunity after HCT was dependent on education of T cell precursors in the thymus. [30][31][32] Furthermore, these observations generated considerable interest in the factors affecting the reconstitution of T cell immunity through thymic-dependent pathways. 33,34 Using phenotypic markers of T cell naivety (primarily the CD45RA antigen), initial studies demonstrated that increasing patient age had an adverse effect on the regeneration of naı¨ve CD4 þ T cells, presumably due to age-related thymic involution, 31 observations that were confirmed using the TCR rearrangement excision circle (TREC) assay to measure thymic output. 35,36 In addition, the thymus has been demonstrated to be...

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Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation

Cited by 111 publications

References 37 publications

Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice

T cell regeneration in pediatric allogeneic stem cell transplantation

Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients

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