Sex Steroid Ablation Enhances Hematopoietic Recovery following Cytotoxic Antineoplastic Therapy in Aged Mice

Abstract

Cytotoxic antineoplastic therapy is widely used in the clinic as a treatment for malignant diseases. The treatment itself, however, leads to long-term depletion of the adaptive immune system, which is more pronounced in older patients, predominantly due to thymic atrophy. We and others have previously shown that withdrawal of sex steroids is able to regenerate the aged thymus and enhance recovery from autologous and allogeneic hematopoietic stem cell transplant. In this study we have examined the effects of sex steroid ablation (SSA) on the recovery of lymphopoiesis in the bone marrow (BM) and thymus following treatment with the chemotherapeutic agent cyclophosphamide (Cy) in middle-aged and old mice. Furthermore, we have also examined the impact of this regeneration on peripheral immunity. SSA enhanced the recovery of BM resident hematopoietic stem cells and lymphoid progenitors and promoted lymphopoiesis. Interestingly, Cy alone caused a profound increase in the recently described common lymphoid progenitor 2 (CLP-2) population in the BM. In the thymus, SSA caused a profound increase in cellularity as well as all intrathymic T-lineage progenitors including early T-lineage progenitors (ETPs) and non-canonical T cell progenitors such as the CLP-2. We also found that these transferred into numerical increases in the periphery with enhanced B and T cell numbers. Furthermore, these lymphocytes were found to have an enhanced functional capacity with no perturbation of the TCR repertoire. Taken together, these results provide the basis for the use of SSA in the clinic to enhance treatment outcomes from cytotoxic antineoplastic therapy.

Thymic Involution: Where Endocrinology Meets Immunology

“…It has been suggested that the thymic stroma is the initial target of androgen-induced thymic atrophy [57,67] ; however, these studies failed to account for the role of bone marrow and thymic lymphoid progenitors, which are also significantly increased following castration [13,16,17] . In the bone marrow, there is improved function in most steps of haematopoiesis from the earliest long-term haematopoietic stem cell (HSC) through to thymic progenitors [pers.…”

Immunodepression and Immunosuppression During Aging

“…This highly dynamical system makes it very sensible and reactive to antigen stimulations, but also to immunosuppressive treatments. Moreover immunostimulatory and rejuvenation treatments are explored to stimulate the immune system in aging or after immunosuppression (Dudakov, Goldberg et al 2009;Lynch, Goldberg et al 2009). Several factors like Keratinocyte growth factor, Growth hormone, cytokines like IL-7, IL-15 or IL2, steroid hormones are implicated in aging process.…”

Feeding the fire: the role of defective bone marrow function in exacerbating thymic involution

“…Adoptive transfer of in vitro generated precursor T cells aids in thymic regeneration and even has long-lasting impacts on the thymus well after the transient progenitors have passed through the thymus; however, the mechanism behind this prolonged regeneration is poorly understood [100]. Among these therapies, sex steroid ablation has beneficial impacts on both the BM and thymus, reversing age-related thymic involution [56] and enhancing BM recovery following chemotherapy [98,101] and bone marrow transplantation [97]. These novel approaches to restore immune capacity through the translation of pre-clinical research are likely to result in the development of strategies to improve the outcome for a variety of patients who incur considerable morbidity and mortality from infections and relapse after high-dose chemotherapy and HSC transplant or following chemotherapy.…”

“…These include: administration of exogenous growth factors and cytokines, such as KGF, growth hormone, ghrelin, IL-7, IL-15, insulin-like growth factor-1, IL-12, or Flt3L; adoptive transfer of T cell precursors generated in vitro; the chemical or surgical ablation of sex steroids ( Figure 3) [45,56,61,97,98] While most of these treatments primarily promote thymopoiesis directly, KGF and sex steroid ablation enhance thymic regeneration by acting on thymic stromal cells [40,45,61,99]. However, the success of growth factors such as IL-7, growth hormone and Flt3L is equivocal [40,44].…”