Effects of Castration on Thymocyte Development in Two Different Models of Thymic Involution

Abstract

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.

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

“…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.…”

Neuro-endocrine-immune Crosstalk and Implications for Cancer Therapy

“…The presence of the androgen receptor (AR) has been documented in lymphoid and nonlymphoid cells of thymus and bone marrow, but not in mature lymphocytes [24,25], suggesting that the major impact of androgens may be on the developmental maturation of T and B cells. Castration of male animals results in significant thymic enlargement and increase in thymus weight and thymocyte number [26][27][28], a phenomenon which is also observed in the setting of defective androgen action (the androgen-resistant testicular feminization mouse [29]. It has also been shown that androgen deprivation stimulates thymic T cell output and results in increased numbers of phenotypically naïve CD4+ and CD8+ peripheral T cells (approximately 2 weeks after castration) and enhances antigen-specific immune responses in postpubertal male mice [30].…”

Aging, B lymphopoiesis, and patterns of leukemogenesis

“…For example bone marrow stromal cells isolated from old mice inefficiently secrete IL-7 (Heng et al, 2005;Stephan et al, 1998). A recent study reported that the production of B cells was rescued following transplantation of aged B lineage progenitors into a young but not an old environment (Labrie et al, 2004).…”