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Sex Steroid Ablation Enhances Hematopoietic Recovery following Cytotoxic Antineoplastic Therapy in Aged Mice¹

Immune Regeneration Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Norwood Immunology, the Australian Stem Cell Centre and the National Health and Medical Research Council of Australia. J.A.D. was supported by a fellowship from the Cancer Council of Victoria.

² Address correspondence and reprint requests to Dr. Jarrod A. Dudakov, Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Wellington Road, Clayton VIC 3800, Australia. E-mail address: Jarrod.Dudakov{at}med.monash.edu.au

³ G.L.G. and J.J.R. contributed equally to this work.

⁴ Current address: Baylor Institute of Immunology Research, 3434 Live Oaks Street, Dallas, TX 75204.

⁵ Abbreviations used in this paper: BM, bone marrow; CLP, common lymphoid progenitor; Cy, cyclophosphamide; DP, double positive; ETP, early T-lineage progenitor; SSA, sex steroid ablation; ELP, early lymphoid progenitor; EPLM, early progenitor with lymphoid and myeloid potential; HSC, hematopoietic stem cell; LSK, Lin^–ScaI⁺ckit⁺; SP, single positive; TN, triple negative; MPP, multipotent progenitor; Treg, regulatory T cell.