title: Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice.
abstract: Cytotoxic antineoplastic therapy is used to treat malignant disease but results in long-term immunosuppression in postpubertal and adult individuals, leading to increased incidence and severity of opportunistic infections. We have previously shown that sex steroid ablation (SSA) reverses immunodeficiencies associated with age and hematopoietic stem cell transplantation in both autologous and allogeneic settings. In this study, we have assessed the effects of SSA by surgical castration on T cell recovery of young male mice following cyclophosphamide treatment as a model for the impact of chemotherapy. SSA increased thymic cellularity, involving all of the thymocyte subsets and early T lineage progenitors. It also induced early repair of damage to the thymic stromal microenvironment, which is crucial to the recovery of a fully functional T cell-based immune system. These functional changes in thymic stromal subsets included enhanced production of growth factors and chemokines important for thymopoiesis, which preceded increases in both thymocyte and stromal cellularity. These effects collectively translated to an increase in peripheral and splenic naive T cells. In conclusion, SSA enhances T cell recovery following cyclophosphamide treatment of mice, at the level of the thymocytes and their stromal niches. This provides a new approach to immune reconstitution following antineoplastic therapy.
authors.affiliation: Immune Regeneration Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Australia. gabbygoldberg@gmail.com
authors.forename: Gabrielle L
authors.initials: GL
authors.lastname: Goldberg
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Dudakov
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Reiseger
authors.forename: Natalie
authors.initials: N
authors.lastname: Seach
authors.forename: Tomoo
authors.initials: T
authors.lastname: Ueno
authors.forename: Katerina
authors.initials: K
authors.lastname: Vlahos
authors.forename: Maree V
authors.initials: MV
authors.lastname: Hammett
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.forename: Tracy S P
authors.initials: TS
authors.lastname: Heng
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boyd
authors.forename: Ann P
authors.initials: AP
authors.lastname: Chidgey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002469:Cell Separation; D003520:Cyclophosphamide / Q000633:toxicity*; D005434:Flow Cytometry; D012739:Gonadal Steroid Hormones / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D016133:Polymerase Chain Reaction; D013256:Steroids; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D012739:Gonadal Steroid Hormones; D013256:Steroids; D003520:Cyclophosphamide