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KGF and androgen blockade work in concert to protect against conditioning regimen‐induced thymic epithelial damage and enhance T‐cell reconstitution following murine BMT
Author(s) -
Kelly Ryan M,
Highfill Steven L,
PanoskaltsisMortari Angela,
Taylor Patricia A,
Boyd Richard L,
Hollaender Georg A,
Blazar Bruce R
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.536
Subject(s) - cd8 , keratinocyte growth factor , t cell , immunology , medicine , blockade , cancer research , receptor , immune system , growth factor
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 pre‐conditioning, reduces TEC injury. Thymocytes and TEC express androgen receptors and exposure to androgen inhibits thymopoiesis. We have investigated whether KGF and leuprolide acetate (Lupron™), given prior to 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 Lupron normalized TEC subset numbers and thymic architecture. Thymopoiesis and thymic output were supranormal, leading to the accelerated peripheral reconstitution of naïve CD4 and CD8 T‐cells with a broad Vβ 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 early post‐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 represent a novel approach to restore thymic function and facilitates the rapid recovery of peripheral T‐cell function following allogeneic BMT. Funding provided by NIH.