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Myeloablative conditioning results in thymic epithelial cell (TEC) injury, slow T-cell reconstitution, and a high risk of opportunistic infections. Keratinocyte growth factor (KGF) stimulates TEC proliferation and, when given preconditioning, reduces TEC injury. Thymocytes and TECs express androgen receptors, and exposure to androgen inhibits thymopoiesis. In this study, we have investigated whether TEC stimulation via preconditioning treatment with KGF and leuprolide acetate (Lupron), 2 clinically approved agents, given only before conditioning would circumvent the profound TEC and associated T-cell deficiency seen in allogeneic bone marrow transplant (BMT) recipients. Only combined treatment with KGF plus leuprolide acetate normalized TEC subset numbers and thymic architecture. Thymopoiesis and thymic output were supranormal, leading to the accelerated peripheral reconstitution of naive CD4 and CD8 T cells with a broad Vbeta repertoire and decreased homeostatic T-cell proliferation. Combined therapy facilitated T:B cooperativity and enabled a B-cell humoral response to a CD4 T cell-dependent neoantigen challenge soon after BMT. In vivo antigen-specific CD8 T-cell responses and clearance of a live pathogen was superior with combined versus individual agent therapy. Thus, KGF combined with androgen blockade represents a novel approach to restore thymic function and facilitates the rapid recovery of peripheral T-cell function after allogeneic BMT.

Original publication

DOI

10.1182/blood-2008-01-136531

Type

Journal article

Journal

Blood

Publication Date

15/06/2008

Volume

111

Pages

5734 - 5744

Keywords

Androgen Antagonists, Animals, Antineoplastic Agents, Hormonal, Bone Marrow Transplantation, Cell Division, Epithelial Cells, Female, Fibroblast Growth Factor 7, Homeostasis, Leuprolide, Listeria monocytogenes, Listeriosis, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Recovery of Function, Spleen, T-Lymphocytes, Thymus Gland, Transplantation Conditioning, Transplantation, Homologous