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* Department of Pathology and Immunology, Central and Eastern Clinical School, Monash University, Melbourne, Australia; and
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York NY 10021
Delayed immune reconstitution in adult recipients of allogeneic hemopoietic stem cell transplantations (HSCT) is related to age-induced thymic atrophy. Overcoming this paucity of T cell function is a major goal of clinical research but in the context of allogeneic transplants, any strategy must not exacerbate graft-vs-host disease (GVHD) yet ideally retain graft-vs-tumor (GVT) effects. We have shown sex steroid ablation reverses thymic atrophy and enhances T cell recovery in aged animals and in congenic bone marrow (BM) transplant but the latter does not have the complications of allogeneic T cell reactivity. We have examined whether sex steroid ablation promoted hemopoietic and T cell recovery following allogeneic HSCT and whether this benefit was negated by enhanced GVHD. BM and thymic cell numbers were significantly increased at 14 and 28 days after HSCT in castrated mice compared with sham-castrated controls. In the thymus, the numbers of donor-derived thymocytes and dendritic cells were significantly increased after HSCT and castration; donor-derived BM precursors and developing B cells were also significantly increased. Importantly, despite restoring T cell function, sex steroid inhibition did not exacerbate the development of GVHD or ameliorate GVT activity. Finally, IL-7 treatment in combination with castration had an additive effect on thymic cellularity following HSCT. These results indicate that sex steroid ablation can profoundly enhance thymic and hemopoietic recovery following allogeneic HSCT without increasing GVHD and maintaining GVT.
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 HL69929, HL72412, CA107096, CA33049, and P20-CA103694 from the National Institutes of Health and awards from the Leukemia and Lymphoma Society, Emerald Foundation, Ryan Gibson Foundation, Elsa U. Pardee Foundation, and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research. The work in the laboratory of R.L.B. was partially supported by Norwood Immunology.
2 Address correspondence and reprint requests to Dr. Gabrielle L. Goldberg at the current address: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY. E-mail address: goldberg{at}mskcc.org
3 M.R.M.v.d.B. and R.L.B. contributed equally.
4 Abbreviations used in this paper: HSC, hemopoietic stem cell; HSCT, HSC transplantation; RTE, recent thymic emigrant; BM, bone marrow; cx, castrated; GVHD, graft-versus-host disease; GVT, graft vs tumor; DTH, delayed-type hypersensitivity; Tg, transgenic; TCD, T cell depleted; DC, dendritic cell; TN, triple negative; DP, double positive; SP, single positive; HPRT, hypoxanthine phosphoribosyltransferase; LHRH, luteinizing hormone-releasing hormone.
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