Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation.
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.
Kelly
Ryan M
RM
Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis 55455, USA.
Highfill
Steven L
SL
Panoskaltsis-Mortari
Angela
A
Taylor
Patricia A
PA
Boyd
Richard L
RL
Holländer
Georg A
GA
Blazar
Bruce R
BR
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology; D016729:Leuprolide / Q000494:pharmacology; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D051523:Fibroblast Growth Factor 7; D016729:Leuprolide