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.
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.
Authors: Serani L H van Dommelen; Alexandra Rizzitelli; Ann Chidgey; Richard Boyd; Ken Shortman; Li Wu Journal: Cell Mol Immunol Date: 2010-02-01 Impact factor: 11.530
Authors: Gabrielle L Goldberg; Johannes L Zakrzewski; Miguel A Perales; Marcel R M van den Brink Journal: Semin Immunol Date: 2007-10-26 Impact factor: 11.130
Authors: Ann P Chidgey; Natalie Seach; Jarrod Dudakov; Maree V Hammett; Richard L Boyd Journal: Semin Immunopathol Date: 2008-11-04 Impact factor: 9.623