Keratinocyte Growth Factor and Stem Cell Factor to Improve Thymopoiesis after Autologous CD34+ Cell Transplantation in Rhesus Macaques

Wils, Evert‐Jan; Aerts‐Kaya, Fatima; Rombouts, Elwin; Mourik, Irene van; Rijken-Schelen, Anita; Visser, Trudi P.; Braakman, Eric; Wagemaker, Gerard; Cornelissen, Jan J.

doi:10.1016/j.bbmt.2011.09.010

Cited by 26 publications

(19 citation statements)

References 58 publications

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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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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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“…A recent study in a non-human primate model showed that adult rhesus macaques, receiving KGF after autologous HSCT, had accelerated hematopoietic recovery, improved thymopoiesis (as evaluated by TREC analysis) and enhanced naïve T cell recovery following transplant. However, the increase in T cell recovery was not associated with an improved immunity against CMV reactivation or an improved response to tetanus toxoid vaccination (129). However, while KGF can also promote the expansion of young and old thymi in mice (68), there is some debate as to its effectiveness in promoting steady-state thymopoiesis in non-human primates (129).…”

Section: Exogenous Strategies To Enhance Thymic Recoverymentioning

confidence: 99%

“…However, the increase in T cell recovery was not associated with an improved immunity against CMV reactivation or an improved response to tetanus toxoid vaccination (129). However, while KGF can also promote the expansion of young and old thymi in mice (68), there is some debate as to its effectiveness in promoting steady-state thymopoiesis in non-human primates (129). …”

Section: Exogenous Strategies To Enhance Thymic Recoverymentioning

confidence: 99%

Thymus: the next (re)generation

Chaudhry

Velardi

Dudakov

et al. 2016

Immunological Reviews

141

131

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Summary As the primary site of T cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way towards the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the pre-clinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.

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“…Pharmacological administration of FGF7 or keratinocyte growth factor (KGF) represses the Ink4a tumor-suppressor gene and partially rejuvenates the murine thymocyte progenitors (Berent-Maoz et al 2012). FGF improves thymopoiesis as well as engraftment following myeloablative stem cell transplantation in rhesus macaques (Wils et al 2012). Palifermin is a pharmaceutical form of recombinant human KGF (rhKGF) (Tamari et al 2012), and its administration leads to regeneration of epithelial tissues after injury (Finch et al 2013).…”

Section: Can Ati Be Reversed Therapeutically?mentioning

confidence: 99%