Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation

• Published in: Blood 2010-02, Vol.115 (5), p.1088-1097
• Main Authors: Kelly, Ryan M., Goren, Emily M., Taylor, Patricia A., Mueller, Scott N., Stefanski, Heather E., Osborn, Mark J., Scott, Hamish S., Komarova, Elena A., Gudkov, Andrei V., Holländer, Georg A., Blazar, Bruce R.
• Format: Article
• Language: English
• Subjects: Adaptive Immunity - drug effects; Adaptive Immunity - immunology; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Benzothiazoles - pharmacology; Biological and medical sciences; Bone Marrow Cells - cytology; Bone Marrow Cells - metabolism; Bone Marrow Cells - radiation effects; Bone Marrow Transplantation; Chemokine CCL21 - metabolism; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Female; Fibroblast Growth Factor 7 - pharmacology; Fluorescent Antibody Technique; Hematologic and hematopoietic diseases; Listeria monocytogenes - immunology; Liver - drug effects; Liver - immunology; Liver - microbiology; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Spleen - drug effects; Spleen - immunology; Spleen - microbiology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Thymus Gland - cytology; Time Factors; Toluene - analogs & derivatives; Toluene - pharmacology; Transplantation; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-05-223198

Myeloablative conditioning before bone marrow transplantation (BMT) results in thymic epithelial cell (TEC) injury, T-cell immune deficiency, and susceptibility to opportunistic infections. Conditioning regimen–induced TEC damage directly contributes to slow thymopoietic recovery after BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given before conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BM transplant recipients. Therefore, we investigated whether the addition of a pharmacologic inhibitor, PFT-β, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. Combined before BMT KGF + PFT-β administration additively restored numbers of cortical and medullary TECs and improved thymic function after BMT, resulting in higher numbers of donor-derived, naive peripheral CD4+ and CD8+ T cells. Radiation conditioning caused a loss of T-cell zone fibroblastic reticular cells (FRCs) and CCL21 expression in lymphoid stroma. KGF + PFT-β treatment restored both FRC and CCL21 expression, findings that correlated with improved T-cell reconstitution and an enhanced immune response against Listeria monocytogenes infection. Thus, transient p53 inhibition combined with KGF represents a novel and potentially translatable approach to promote rapid and durable thymic and peripheral T-cell recovery after BMT.