Strategies for reconstituting and boosting T cell-based immunity following haematopoietic stem cell transplantation: pre-clinical and clinical approaches

Chidgey, Ann Patricia; Seach, Natalie Louise; Dudakov, Jarrod A; Hammett, Maree Vanessa; Boyd, Richard

doi:10.1007/s00281-008-0140-5

Cited by 25 publications

(30 citation statements)

References 213 publications

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“…24 Preservation of the thymic epithelium by new therapeutic approaches has, therefore, lately received more attention. [27][28][29] We evaluated thymic function by both the frequency of sjTREC + T cells and the sjTREC content per milliliter of peripheral blood. The latter estimate was added in order to correct for peripheral homeostatic T-cell expansion, which may result in dilution of sjTREC and subsequent underestimation of thymic function.…”

Section: Discussionmentioning

confidence: 99%

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Wils¹,

Holt²,

Broers³

et al. 2011

Haematologica

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BackgroundRecovery of thymopoiesis after allogeneic hematopoietic stem cell transplantation is considered pivotal for full immune competence. However, it is still unclear to what extent insufficient recovery of thymopoiesis predicts for subsequent opportunistic infections and non-relapse mortality. Design and MethodsA detailed survey of all post-engraftment infectious complications, non-relapse mortality and overall survival during long-term follow-up was performed in 83 recipients of allogeneic stem cell grafts after myeloablative conditioning. Recovery of thymopoiesis was assessed using analysis of signal joint T-cell receptor rearrangement excision circles. The impact of recovery of thymopoiesis at 2, 6, 9 and 12 months post-transplantation on clinical outcome beyond those time points was evaluated by univariate and multivariate Cox regression analyses. ResultsThe cumulative incidence of severe infections at 12 months after transplantation was 66% with a median number of 1.64 severe infectious episodes per patient. Patients in whom thymopoiesis did not recover were at significantly higher risk of severe infections according to multivariable analysis. Hazard ratios indicated 3-and 9-fold increases in severe infections at 6 and 12 months, respectively. Impaired recovery of thymopoiesis also translated into a higher risk of non-relapse mortality and outweighed pre-transplant risk factors including age, donor type, and disease risk-status. ConclusionsThese results indicate that patients who fail to recover thymopoiesis after allogeneic hematopoietic stem cell transplantation are at very high risk of severe infections and adverse clinical outcome.Key words: thymopoiesis, opportunistic infections, transplantation outcome, TREC. Haematologica 2011;96(12):1846-1854. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Wils E-J, van der Holt B, Broers AEC, Posthumus-van Sluijs SJ, Gratama J-W, Braakman E and Cornelissen JJ. Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients. Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

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Section: Discussionmentioning

confidence: 99%

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Wils¹,

Holt²,

Broers³

et al. 2011

Haematologica

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“…For example, keratinocyte growth factor and sex steroid ablation have been reported to improve thymopoiesis by restoration of the functions of thymic epithelial cells [8][9][10][11][12][13]. Transplantation of cultured thymus fragments has been used to provide the thymic microenvironment for T-cell regeneration in patients and experimental animals with T-cell deficiencies or as a method for the induction of tolerance in organ transplantation [7,[14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells

Lai

Jin

2009

Stem Cells

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Thymopoiesisis regulated by the thymic microenvironment, of which epithelial cells are the major components. Both cortical and medullary thymic epithelial cells (TECs) have been shown to arise from a common progenitor cell. Here we show for the first time that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to differentiate into cells that have the phenotype of thymic epithelial progenitors (TEPs). When placed in vivo, these mESC-derived TEPs self-renew, develop into TECs, and reconstitute the normal thymic architecture. Functionally, these ESC-derived TEPs enhanced thymocyte regeneration after bone marrow transplantation and increased the number of functional naive splenic T cells. In addition to providing a model to study the molecular events underlying thymic epithelial cell development, the ability to selectively induce the development of TEPs in vitro from mESCs has important implications regarding the prevention and/or treatment of primary and secondary T-cell immunodeficiencies.

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“…47,48 Many efforts have been made to boost thymopoiesis or to develop therapeutic interventions to generate T cells in vitro from BM progenitors. 49,50 This report showed a very refined myeloid progenitor population in mouse BM that lacks B lymphoid potential but could readily generate bona fide T cells after transfer to a T-cell biased environment, such as OP9DL coculture or intrathymic transplantation. Our finding therefore provides an additional source of BM progenitors outside the traditional lymphoid progenitor pool that also possesses T-lineage potential and might be used to generate T cells ex vivo.…”

Section: Discussionmentioning

confidence: 93%

Identification of Flt3+CD150− myeloid progenitors in adult mouse bone marrow that harbor T lymphoid developmental potential

Anthony

Chavez

et al. 2011

Blood

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Common myeloid progenitors (CMPs) were first identified as progenitors that were restricted to myeloid and erythroid lineages. However, it was recently demonstrated that expression of both lymphoidand myeloid-related genes could be detected in myeloid progenitors. Furthermore, these progenitors were able to give rise to T and B lymphocytes, in addition to myeloid cells. Yet, it was not known whether these progenitors were multipotent at the clonogenic level or there existed heterogeneity within these progenitors with different lineage potential. Here we report that previously defined CMPs possess T-lineage potential, and that this is exclusively found in the Flt3 ؉ CD150 -subset of CMPs at the clonal level. In contrast, we did not detect B-lineage potential in CMP subsets. Therefore, these IntroductionAll blood lineages ultimately arise from hematopoietic stem cells (HSCs). HSCs, along with downstream multipotent progenitors (MPPs) and lymphoid-primed MPPs (LMPPs), are present within a small pool of bone marrow (BM) cells with the surface phenotype of LSK (Lineage-marker Ϫ Sca1 ϩ Kit ϩ ). 1,2 Outside of LSK progenitors, a population of BM progenitors characterized as Lin -Sca1 -Kit ϩ CD34 ϩ Fc␥R low was found to be able to give rise to myeloid or erythroid cells, but appeared to lack the ability to generate lymphoid cells in in vivo and in vitro assays. 3 Thus it appeared these cells were restricted to myeloid/erythroid lineages. Because myeloid and erythroid potential was present at the clonogenic level within this population, these progenitors were termed common myeloid progenitors, or CMPs. 3 Granulocyte/monocyte progenitors (GMPs) and megakaryocyte/erythrocyte progenitors (MEPs) were also identified. As GMPs and MEPs possessed a more restricted developmental potential than CMPs, it was postulated that GMPs and MEPs were downstream of CMPs and that CMPs gave rise to myeloid cells or erythroid cells via GMPs or MEPs, respectively. 3 More recent work has suggested that a degree of lymphoid potential persists in myeloid progenitors. First, myeloid progenitors transduced with stabilized ␤-catenin were able to give rise to T and B lymphocytes. 4 Using Ikaros-reporter mice, 5 expression of both lymphoid-and myeloid-related genes was detected in Lin -Sca1 -Kit ϩ GFP Ikarosϩ BM cells, suggesting the existence of lymphoidmyeloid progenitors within the previously thought myeloid/ erythroid-restricted progenitor compartment. 6 It was further shown that some of these progenitors were able to give rise to T and B lymphocytes, in addition to myeloid cells, at the population level. 6 However, it was not known whether individual cells within this population were multipotent at the clonal level. Alternatively, there might be heterogeneity within this population where subsets of progenitors possess different lineage potentials. Indeed, recent work has clearly established heterogeneity for myeloid and erythroid lineage potentials among CMPs. CMPs can be subdivided into CD150 -(preGM) and CD150 ϩ (preMegE) populations, with ...

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Strategies for reconstituting and boosting T cell-based immunity following haematopoietic stem cell transplantation: pre-clinical and clinical approaches

Cited by 25 publications

References 213 publications

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients

Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells

Identification of Flt3+CD150− myeloid progenitors in adult mouse bone marrow that harbor T lymphoid developmental potential

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