Onset of thymic recovery and plateau of thymic output are differentially regulated after stem cell transplantation in children

Eyrich, Matthias; Wollny, Gernot; Tzaribaschev, Nikolaj; Dietz, Klaus; Brügger, Dorothee; Bader, Peter; Lang, Peter; Schilbach, Karin; Winkler, Beate; Niethammer, D.; Schlegel, Paul G.

doi:10.1016/j.bbmt.2004.12.001

Cited by 43 publications

(40 citation statements)

References 39 publications

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“…As previously reported, 29 the initiation of regeneration of naive T lymphocytes and thymic function appeared by 6 months post transplant among the allogeneic recipients. 26,29 The recovery of the naive CD4 þ T lymphocytes post HSCT has been shown to be protracted also in children. 30,31 In previous studies, data on immune reconstitution has been compared with either healthy, age-matched controls 31 or within subgroups.…”

Section: Discussionsupporting

confidence: 54%

“…32,33 Also in our study, aGVHD did not affect the regeneration of the naive T cells or TRECs post HSCT. However, and as previously reported, [14][15][16]29 low TREC levels did associate with extensive cGVHD post HSCT. Patients with cGVHD have a reduced capacity to produce naive CD4 þ T cells 34 because of thymic epithelial injury by GVHD and immunosuppressive drugs.…”

Section: Discussionmentioning

confidence: 62%

“…26,29 In our data, the lowest values appeared to coincide in the sibling and unrelated groups during the first 3 months post HSCT. As previously reported, 29 the initiation of regeneration of naive T lymphocytes and thymic function appeared by 6 months post transplant among the allogeneic recipients. 26,29 The recovery of the naive CD4 þ T lymphocytes post HSCT has been shown to be protracted also in children.…”

Section: Discussionmentioning

confidence: 63%

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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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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 63%

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T cell regeneration in pediatric allogeneic stem cell transplantation

Olkinuora

Talvensaari

Kaartinen

et al. 2007

Bone Marrow Transplant

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“…A negative correlation between increasing age and numbers of naïve CD4 þ T cells and TRECs after autologous and allogeneic SCT or chemotherapy has been reported in a variety of studies. [75][76][77][78][79] Some studies in MAC-SCT setting have shown age as the main determinant of T-cell reconstitution after SCT. Eyrich et al 79 analyzed in a series of 164 pediatric recipients of allogeneic myeloablative transplantation (median age 7.5 years, range 0.3-22.6 years) the effect of recipient age, conditioning regimen, type of donor and graft, stem cell dose and GvHD on the onset and the plateau of thymic output after transplantation.…”

Section: Patient's Agementioning

confidence: 99%

Immune reconstitution after allogeneic stem cell transplantation with reduced-intensity conditioning regimens

2007

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Reduced-intensity conditioning (RIC) regimens have been increasingly used as an alternative to conventional myeloablative conditioning (MAC) regimens for elderly patients, for patients medically infirm to qualify for conventional allogeneic stem cell transplantation (SCT), and for disorders in which traditional MAC-SCT are associated with high rates of nonrelapse mortality. One of the theoretical advantages of RIC-SCT is that it might lend to better immune reconstitution after transplantation due to less damage of the thymus, allowing regeneration of naive T cells derived from prethymic donor stem cells, and due to the proliferation of immunologically competent host T cells that survive the conditioning regimen. Although limited, studies comparing immune recovery following RIC and MAC-SCT have been insightful. One of the main difficulties of these studies is the current spectrum of RIC protocols, which vary considerably in myeloablative and immunosuppressive potential, resulting in apparently contradictory findings. In spite of this, most reports have shown significant quantitative and/or qualitative differences in T-and B-cell reconstitution after RIC-SCT in comparison with conventional SCT. This paper will review current knowledge of immune reconstitution following RIC-SCT.

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“…This suggests homeostatic proliferation as the substantial mechanism of T-cell repopulation in early phases after treatment, as described during lymphopenia. 35 Other investigators have proposed that the rapid proliferation observed after BMT is mainly associated with the occurrence of GVDH and infection. 36 In this regard, it is important to note that most GT patients did not experience infectious complications, and the GVHD-related bias is unlikely to occur because of the autologous nature of the transplant.…”

Section: Discussionmentioning

confidence: 99%

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

Selleri

Brigida

Casiraghi

et al. 2011

Journal of Allergy and Clinical Immunology

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Background: Gene therapy (GT) with hematopoietic stem cells is a promising treatment for inherited immunodeficiencies. Objectives: Limited information is available on the relative contribution of de novo thymopoiesis and peripheral expansion to T-cell reconstitution after GT as well as on the potential effects of gene transfer on hematopoietic stem cells and lymphocyte replicative lifespan. We studied these issues in patients affected by adenosine deaminase severe combined immune deficiency after low-intensity conditioning and reinfusion of retrovirally transduced autologous CD34 1 cells. Methods: Immunophenotype, proliferative status, telomere length, and T-cell receptor excision circles were investigated at early and late time points (up to 9 years) after GT treatment. Control groups consisted of pediatric healthy donors and patients undergoing allogeneic bone marrow transplantation (BMT). Results: We observed no telomere shortening in the bone marrow compartment and in granulocytes, whereas peripheral blood naive T cells from both GT and BMT patients showed a significant reduction in telomere length compared with healthy controls. This was in agreement with the presence of a high fraction of actively cycling naive and memory T cells and lower T-cell receptor excision circles. Conclusion: These data indicate that T-cell homeostatic expansion contributes substantially to immune reconstitution, like BMT, and is not associated with senescence in the stem cell compartment. (J Allergy Clin Immunol 2011;127:1368-75.)

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Onset of thymic recovery and plateau of thymic output are differentially regulated after stem cell transplantation in children

Cited by 43 publications

References 39 publications

T cell regeneration in pediatric allogeneic stem cell transplantation

T cell regeneration in pediatric allogeneic stem cell transplantation

Immune reconstitution after allogeneic stem cell transplantation with reduced-intensity conditioning regimens

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

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