Sex Steroid Ablation Enhances Lymphoid Recovery Following Autologous Hematopoietic Stem Cell Transplantation

Goldberg, Gabrielle L.; Sutherland, Jayne S.; Hammet, Maree V.; Milton, Morag K.; Heng, Tracy; Chidgey, Ann Patricia; Boyd, Richard

doi:10.1097/01.tp.0000183962.64777.da

Cited by 96 publications

(59 citation statements)

References 81 publications

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“…Since immunity can be restored faster following chemotherapy and hemopoietic stem cell transplantation, using reversible sex steroid blockade (52,(75)(76)(77)(78), hemopoietic stem cell transplantation may be rendered safe enough to reinstate tolerance in some autoimmunity patients given a similar though less myeloablative regime. However, any underlying stromal defects must be considered, as their effects could be magnified following thymic hypertrophy, increasing the risk of relapse, particularly if stromal cells are incapable of expansion.…”

Section: Discussionmentioning

confidence: 99%

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Fletcher

Seach²,

Reiseger³

et al. 2009

The Journal of Immunology

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The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-κB2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class IIhigh (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.

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Section: Discussionmentioning

confidence: 99%

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Fletcher

Seach²,

Reiseger³

et al. 2009

The Journal of Immunology

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“…B cell development is also negatively regulated by sex steroids and again removal of sex steroids enhances B cell development and reverses age-related decreases in B cell production [20;21]. Sex steroid ablation results in a significant increase in B and T cell reconstitution after both autologous [22] and allogeneic [23] HSCT and in humans who underwent reversible chemical castration using an LHRH agonist [24].…”

Section: Hormones Growths Factors and Cytokinesmentioning

confidence: 99%

Enhancing T cell reconstitution after hematopoietic stem cell transplantation: A brief update of the latest trends

Zakrzewski

Goldberg

Smith

et al. 2008

Blood Cells, Molecules, and Diseases

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Hematopoietic stem cell transplantation (HSCT) is associated with a period of immune incompetence that particularly affects the T cell lineage. Strategies to enhance T cell reconstitution could significantly improve the survival of HSCT recipients by decreasing the incidence of fatal infectious complications and by enhancing graft-versus-tumor activity. In recent years, a variety of promising strategies have been established in preclinical models to improve T cell recovery in particular after allogeneic T cell-depleted HSCT, without aggravating graft-versus-host disease while preserving or even improving graft-versus-tumor activity. These therapies include treatment with keratinocyte growth factor (KGF), growth hormone (GH), LHRH agonists, interleukin 7 (IL-7) and interleukin 15 (IL-15). Thanks to the establishment of Notch-based culture systems, adoptive cellular therapies with T lineage-committed precursor cells have become feasible, since early T cell progenitors can now easily be generated in vitro in large quantities and have been proven to be very effective in enhancing T cell reconstitution and anti-tumor activity after allogeneic T cell-depleted HSCT. The translation of most of these strategies into clinical trials is likely and in some cases Phase I/II studies are already underway.

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“…Interestingly, sex-associated hormones, including androgens and estrogen, have been directly implicated in regulating hematopoietic cell function. [2][3][4] During the course of our functional analyses of HSCs using the recently developed NOD/SCID/ IL-2Rg c -null (NSG) mice, 5 we observed that the recipient sex plays a critical role in the engraftment and proliferation of human HSCs. Specifically, female NSG mice are far superior to their male counterparts in engrafting and detection of single human HSCs.…”

Section: Introductionmentioning

confidence: 99%

Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients

Notta

Doulatov

Dick

2010

Blood

115

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Repopulation of immunodeficient mice remains the primary method to assay human hematopoietic stem cells (HSCs). Here we report that female NOD/SCID/IL-2Rg c -null mice are far superior in detecting human HSCs (Lin ؊ CD34 ؉ CD38 ؊ CD90 ؉ CD45RA ؊ ) compared with male recipients. When multiple HSCs were transplanted, female recipients displayed a trend (1.4-fold) toward higher levels of human chimerism (female vs male: injected femur, 44.4 ؎ 9.3 vs 32.2 ؎ 6.2; n ‫؍‬ 12 females, n ‫؍‬ 24 males; P ‫؍‬ .1). IntroductionThe dynamic interplay between donor hematopoietic stem cells (HSCs) and the recipient microenvironment governs the survival and proliferation of HSCs in a transplantation setting. A complex network of cells within the microenvironment regulates HSC function via direct interaction or secretion of cytokines that act in an autocrine or paracrine manner. 1 However, the effects on HSCs by molecules that communicate in an endocrine fashion, such as steroid hormones, remain understudied. Interestingly, sex-associated hormones, including androgens and estrogen, have been directly implicated in regulating hematopoietic cell function. [2][3][4] During the course of our functional analyses of HSCs using the recently developed NOD/SCID/ IL-2Rg c -null (NSG) mice, 5 we observed that the recipient sex plays a critical role in the engraftment and proliferation of human HSCs. Specifically, female NSG mice are far superior to their male counterparts in engrafting and detection of single human HSCs. Methods Collection of human CBHuman cord blood (CB) was collected according to guidelines established by Trillium Health Center and University Health Network. Mononuclear cells from pooled CBs were harvested using a Ficoll gradient and subsequently depleted of mature cells (Lin Ϫ ) via negative selection using StemSep system (StemCell Technologies). Cells were viably frozen in 10% dimethyl sulfoxide solution and stored at Ϫ80°C or Ϫ150°C. Fluorescence-activated cell sortingFreshly thawed Lin Ϫ CB was stained with CD34 allophycocyanin, CD38 PC7, CD45RA fluorescein isothiocyanate, and CD90 phycoerythrin in phosphate-buffered saline plus 5% fetal calf serum at a concentration of 10 7 cells/mL for 30 minutes at 4°C. Cells were sorted on FACSAria II (BD Biosciences), and purities of more than 99% were commonly achieved in postsort analysis (data not shown). Cells were counted in Trypan blue before transplantation and resuspended in 25 L of Iscove modified Dulbecco medium/mouse in a 28.5-gauge 0.5-mL insulin syringe. Xenotransplantation and detection of human chimerismAll animal experiments were performed with the approval of the Animal Care Committee at the University Health Network. Ten-to 12-week-old NSG mice were sublethally irradiated (200-225 cGy) 24 hours before transplantation. Cells were transplanted intrafemorally as previously described. 6 Briefly, a 27-gauge needle was used to drill a hole in the right femur, which was followed by injection of cells using a 28.5-gauge insulin syringe. Mice were killed 16 to 20 weeks ...

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Sex Steroid Ablation Enhances Lymphoid Recovery Following Autologous Hematopoietic Stem Cell Transplantation

Abstract: These data suggest that sex steroid ablation significantly enhances lymphopoiesis following auto-HSCT providing a new strategy for posttransplant immune reconstitution.

Cited by 96 publications

References 81 publications

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

Enhancing T cell reconstitution after hematopoietic stem cell transplantation: A brief update of the latest trends

Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgc-null recipients

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