Sex steroid blockade enhances thymopoiesis by modulating Notch signaling

Velardi, Enrico; Tsai, Jennifer J.; Holland, Aliya; Wertheimer, Tobias; Yu, Vionnie W.C.; Zakrzewski, Johannes L.; Tuckett, Andrea Z.; Singer, Natalie V.; West, Mallory L.; Smith, Odette M.; Young, Lauren; Kreines, Fabiana M.; Levy, Emily R.; Boyd, Richard; Scadden, David T.; Dudakov, Jarrod A; Brink, Marcel R.M. van den

doi:10.1084/jem.20131289

Cited by 101 publications

(99 citation statements)

References 40 publications

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“…Sex steroids influence thymopoiesis through direct inhibition of Notch ligand in cortical thymic epithelial cells. In accordance with previous findings that Notch ligand is critical for commitment and differentiation of T-cell progenitors, sex steroid ablation by LHRH receptor antagonism enhanced expression of Notch ligand, resulting in rapid promotion of thymopoiesis [7]. Therefore, these strategies could not only improve thymic regeneration after allo-HSCT but also boost immune function.…”

Section: Novel Strategies For Allo-hsctsupporting

confidence: 88%

Overview: New Modality for Cancer Treatment

Nishikawa¹

2015

Oncology

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Cancer immunotherapy is now becoming a promising modality of cancer treatment upon the clinical successes of adoptive T-cell transfer and immune checkpoint blockade. At the 30th Nagoya International Cancer Treatment Symposium, Marcel R.M. van den Brink (Memorial Sloan Kettering Cancer Center, MSKCC, New York, N.Y., USA) showed novel strategies to control malignant relapse and graft-versus-host disease, both major obstacles for clinical benefits in allogeneic hematopoietic stem cell transplantation. Alexander M. Lesokhin (MSKCC, New York, N.Y., USA) presented an overview of immune checkpoint blockade, particularly focusing on hematologic malignancies stressing the importance of immunomonitoring to identify biomarkers.

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Section: Novel Strategies For Allo-hsctsupporting

confidence: 88%

Overview: New Modality for Cancer Treatment

Nishikawa¹

2015

Oncology

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“…As a consequence, efforts to improve thymic reconstitution using cytokines [IL7 (25), SCF, KFG (26,27), FLT3L (28)] or hormones [growth hormone (29), thyroid-stimulating hormone (30), and ablation of sex hormones (31)] are only likely to be effective if they selectively act on the thymic microenvironment or mimic signals given by the thymic epithelial cells to developing thymocytes. Transplantation of committed T-cell progenitors together with HSCT, as shown before with mouse hematopoietic cells cultured ex vivo on OP9-DL1 expressing stromal supportwhich provide the cells with the Notch signals required to direct T-cell development (32)-as well as diminishing the influence of male sex hormones known to deregulate intrathymic Notch ligand DLL4 (31) may work well to improve thymic function and support diverse TCR repertoire formation.…”

Section: Discussionmentioning

confidence: 99%

Development of a diverse human T-cell repertoire despite stringent restriction of hematopoietic clonality in the thymus

Brugman

Wiekmeijer

Eggermond

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The fate and numbers of hematopoietic stem cells (HSC) and their progeny that seed the thymus constitute a fundamental question with important clinical implications. HSC transplantation is often complicated by limited T-cell reconstitution, especially when HSC from umbilical cord blood are used. Attempts to improve immune reconstitution have until now been unsuccessful, underscoring the need for better insight into thymic reconstitution. Here we made use of the NOD-SCID-IL-2Rγ−/− xenograft model and lentiviral cellular barcoding of human HSCs to study T-cell development in the thymus at a clonal level. Barcoded HSCs showed robust (>80% human chimerism) and reproducible myeloid and lymphoid engraftment, with T cells arising 12 wk after transplantation. A very limited number of HSC clones (<10) repopulated the xenografted thymus, with further restriction of the number of clones during subsequent development. Nevertheless, T-cell receptor rearrangements were polyclonal and showed a diverse repertoire, demonstrating that a multitude of T-lymphocyte clones can develop from a single HSC clone. Our data imply that intrathymic clonal fitness is important during T-cell development. As a consequence, immune incompetence after HSC transplantation is not related to the transplantation of limited numbers of HSC but to intrathymic events.H ematopoietic stem cell transplantation (HSCT) has become common clinical practice in the treatment of leukemia, lymphoma, and certain inherited immune and metabolic disorders. After transplantation there is an immediate need for de novo production of granulocytes, erythrocytes, and platelets, referred to as "hematopoietic reconstitution," later followed by recovery of lymphocyte numbers, termed "immune reconstitution." Although often successful, HSCT is associated with a number of complications arising from poor immune reconstitution, which presents one of the most important causes of morbidity after HSCT (1, 2). Poor myeloid reconstitution is directly linked to low numbers of HSCs in the transplant, but the reasons for poor immune and, in particular, T-lymphocyte reconstitution are much less clear.A study on the application of antithymocyte globulin in cord blood transplantation showed that antithymocyte globulin administration in pretransplantation conditioning results in decreased T-cell reconstitution and survival (3), indicating the need for a better understanding of de novo T-cell development after HSCT. As T cells develop in the thymus, in contrast to all other blood lineages that develop in the bone marrow (BM), HSCderived progenitors need to seed the thymus. Earlier work in mice has indicated that relatively few progenitors seed the thymus (4, 5), yet their numbers and the subsequent fate of the progeny derived from an HSC clone has remained elusive. The nature of the thymusseeding cell has been subject of much debate, certainly in humans. CD34+ cells (6, 7), CD34 (8), and others have been proposed as thymus-seeding cells in the human situation. In contrast to mice, the earliest hu...

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“…For example, sex steroids in the thymus seem to decrease the expression of Notch ligand, which is an important driver of T-cell development. 59 Studies both in man and mouse demonstrated that SSA using castration (in mice) or the luteinizing hormone releasing hormone (LHRH) agonist Leuprolide after auto-and allo-HSCT or cytoablative therapy per se results in: (1) increased numbers of lymphoid precursors and import of thymic precursors into the thymus, (2) improved thymopoiesis, (3) enhanced B lymphopoiesis, and (4) improved recovery of functional immunity. 51 As mentioned above, a clinical trial combining SSA with leuprolide and KGF in HSCT recipients is underway.…”

Section: Sex Steroid Ablation (Ssa)mentioning

confidence: 99%