Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice.
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.
Goldberg
Gabrielle L
GL
Immune Regeneration Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Australia. gabbygoldberg@gmail.com
Dudakov
Jarrod A
JA
Reiseger
Jessica J
JJ
Seach
Natalie
N
Ueno
Tomoo
T
Vlahos
Katerina
K
Hammett
Maree V
MV
Young
Lauren F
LF
Heng
Tracy S P
TS
Boyd
Richard L
RL
Chidgey
Ann P
AP
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
D000970:Antineoplastic Agents; D012739:Gonadal Steroid Hormones; D013256:Steroids; D003520:Cyclophosphamide