Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/60853
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | 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 |
Author: | Kelly, R. Goren, E. Taylor, P. Mueller, S. Stefanski, H. Osborn, M. Scott, H. Komarova, E. Gudkov, A. Hollander, G. Blazar, B. |
Citation: | Blood, 2010; 115(5):1088-1097 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2010 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Ryan M. Kelly, Emily M. Goren, Patricia A. Taylor, Scott N. Mueller, Heather E. Stefanski, Mark J. Osborn, Hamish S. Scott, Elena A. Komarova, Andrei V. Gudkov, Georg A. Holländer and Bruce R. Blazar |
Abstract: | 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. |
Keywords: | Liver Spleen Thymus Gland T-Lymphocytes Bone Marrow Cells Epithelial Cells Animals Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice Listeria monocytogenes Toluene Membrane Proteins Proto-Oncogene Proteins Fluorescent Antibody Technique Bone Marrow Transplantation Time Factors Female Male Tumor Suppressor Protein p53 Apoptosis Regulatory Proteins Fibroblast Growth Factor 7 Benzothiazoles Chemokine CCL21 Adaptive Immunity Bcl-2-Like Protein 11 |
Rights: | © 2010 by The American Society of Hematology |
DOI: | 10.1182/blood-2009-05-223198 |
Published version: | http://dx.doi.org/10.1182/blood-2009-05-223198 |
Appears in Collections: | Aurora harvest 5 Medicine publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.