Biomedical subjects

Gabrielle L Goldberg

Publications and source records attributed to Gabrielle L Goldberg.

5 recordsLinked to original sources

PubMed2005

Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation.

BACKGROUND: Autologous hematopoietic stem cell transplantation (auto-HSCT) patients experience long-term immunosuppression, which increases susceptibility to infection and relapse rates due to minimal residual disease (MRD). Sex steroid (SS) ablation is known to reverse age-related thymic atrophy and decline in B-cell production METHODS: This study used a congenic HSCT mouse model to analyze the effects of SS ablation (through surgical castration) on immune reconstitution and growth factor production following auto-HSCT. Bone marrow (BM) and thymic stromal cell (TSCs) populations were analyzed using RT-PCR and were tested for the production of growth factors previously implicated in immune reconstitution or age-relate immune degeneration RESULTS: Castration increased bone marrow (BM), thymic, and splenic cellularity following auto-HSCT. HSC number and common lymphoid precursor (CLP) frequency and number were increased in castrated mice. B cell precursor numbers were also significantly increased in the BM of these mice. Triple negative, double positive and single positive thymocytes were increased following HSCT and castration, as were thymic dendritic cells and natural killer T (NKT) cells. This enhanced lymphoid reconstitution of the primary immune organs leads to a significant increase in splenic T and B cells 42 days after HSCT. The molecular mechanisms behind the enhanced reconstitution were also studied. TGF-beta1 was decreased in castrated mice compared to sham-castrated controls in TSCs and BM cells. TSC production of IL-6 was also decreased in castrated mice CONCLUSIONS: These data suggest that sex steroid ablation significantly enhances lymphopoiesis following auto-HSCT providing a new strategy for posttransplant immune reconstitution.

Androgens↗

PubMed2005

Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions.

Age Factors↗

PubMed2005

Effects of castration on thymocyte development in two different models of thymic involution.

Age-associated thymic involution is accompanied by decreased thymic output. This adversely affects general immune competence and T cell recovery following cytoreductive treatments such as chemotherapy. A causal link between increasing sex steroids and age-related thymic atrophy is well established. Although castration has been demonstrated to regenerate the atrophied thymus, little is known about how this is initiated or the kinetics of thymocyte regeneration. The present study shows that although castration impacts globally across thymocyte development in middle-aged mice, the regenerative effects are initiated in the immature triple-negative compartment and early T lineage progenitors (ETP). Specifically, there was a reduction in number of ETP with age, which was restored following castration. There was, however, no change in ETP reconstitution potential in ETP at this age or following castration. Furthermore, in a chemotherapy-induced model of thymic involution, we demonstrate castration enhances intrathymic proliferation and promotes differentiation through the triple-negative program. Clinically, reversible sex steroid ablation is achieved hormonally, and thus presents a means of ameliorating immune inadequacies, for example, following chemotherapy for bone marrow transplantation. By improving our understanding of the kinetics of thymic recovery, this study will allow more appropriate timing of therapy to achieve maximal reconstitution, especially in the elderly.

Aging↗

PubMed2005

Activation of thymic regeneration in mice and humans following androgen blockade.

The thymus undergoes age-related atrophy, coincident with increased circulating sex steroids from puberty. The impact of thymic atrophy is most profound in clinical conditions that cause a severe loss in peripheral T cells with the ability to regenerate adequate numbers of naive CD4+ T cells indirectly correlating with patient age. The present study demonstrates that androgen ablation results in the complete regeneration of the aged male mouse thymus, restoration of peripheral T cell phenotype and function and enhanced thymus regeneration following bone marrow transplantation. Importantly, this technique is also applicable to humans, with analysis of elderly males undergoing sex steroid ablation therapy for prostatic carcinoma, demonstrating an increase in circulating T cell numbers, particularly naive (TREC+) T cells. Collectively these studies represent a fundamentally new approach to treating immunodeficiency states in humans.

Aged↗

PubMed2005

Controlling the thymic microenvironment.

T-cell development in the thymus is a stepwise process, mediated by a variety of stromal cells in different regions of the organ. Although the cellular composition of the thymic microenvironment has been known for over a decade, the molecular cues that govern its formation are only beginning to be understood. Stromal-derived chemokines attract T-cell precursors to the thymus and direct maturing thymocytes to appropriate niches for their further development. Reciprocal signals from developing T cells provide crosstalk that is essential for establishment and maintenance of the thymic microenvironment. Elucidation of the molecular players involved and their context within the organ is the challenge for the field today. This knowledge could then be translated to clinical restoration of thymic function and T-cell reconstitution.

Animals↗