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* Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Department of Immunology, Weill Cornell Medical College, New York, NY 10021; and
Monash Immunology and Stem Cell Laboratories, Melbourne, Victoria, Australia
Posttransplant immunodeficiency, specifically a lack of T cell reconstitution, is a major complication of allogeneic bone marrow transplantation. This immunosuppression results in an increase in morbidity and mortality from infections and very likely contributes to relapse. In this study, we demonstrate that sex steroid ablation using leuprolide acetate, a luteinizing hormone-releasing hormone agonist (LHRHa), increases the number of lymphoid and myeloid progenitor cells in the bone marrow and developing thymocytes in the thymus. Although few differences are observed in the peripheral myeloid compartments, the enhanced thymic reconstitution following LHRHa treatment and allogeneic bone marrow transplantation leads to enhanced peripheral T cell recovery, predominantly in the naive T cell compartment. This results in an increase in T cell function in vivo and in vitro. Graft-versus-host-disease is not exacerbated by LHRHa treatment and graft-versus-tumor activity is maintained. Because LHRHa allows for reversible (and temporary) sex steroid ablation, has a strong safety profile, and has been clinically approved for diseases such as prostate and breast cancer, this drug treatment represents a novel therapeutic approach to reversal of thymic atrophy and enhancement of immunity following immunosuppression.
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 research was supported by National Institutes of Health Grants R01-HL069929 (M.v.d.B.), R01-CA107096 (MvdB), R01-AI080455 (M.v.d.B.) and P01-CA33049 (M.v.d.B.). Support was also received from the Ryan Gibson Foundation (Dallas, TX), the Elsa U. Pardee Foundation (Midland, MI), the Byrne Foundation (Etna, NH), the Emerald Foundation (New York, NY), and The Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research (Richmond, VA), The Bobby Zucker Memorial Fund (Phoenixville, PA), and The Lymphoma Foundation (New York, NY). G.L.G. is supported by the P20 Memorial Sloan-Kettering Cancer Center Aging and Cancer Institution grant from the National Institutes of Health.
2 C.G.K. and R.A.N. contributed equally.
3 Address correspondence and reprint requests to Dr. Marcel van den Brink, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021. E-mail address: vandenbm{at}mskcc.org
4 Abbreviations used in this paper: BMT, bone marrow transplantation; HSC, hematopoietic stem cell; ER
, estrogen receptor ; LHRH, luteinizing hormone-releasing hormone; BN, bone marrow; GVDH, graft-versus-host disease; GVT, graft-versus-tumor; TCD, T cell depleted; LSK, lineage–Sca-1+c-kit+; CLP, common lymphoid progenitor; TN, triple negative; ETP, early T cell progenitor; KGF, keratinocyte growth factor; NP, 4-hydroxy-3-nitrophenyl; CGG, chicken 
-globulin; DP, double positive; SP, single positive.
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