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.
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. Keratino...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2010
|
| _version_ | 1797099541718106112 |
|---|---|
| author | Kelly, R Goren, E Taylor, P Mueller, SN Stefanski, H Osborn, M Scott, H Komarova, E Gudkov, A Holländer, G Blazar, B |
| author_facet | Kelly, R Goren, E Taylor, P Mueller, SN Stefanski, H Osborn, M Scott, H Komarova, E Gudkov, A Holländer, G Blazar, B |
| author_sort | Kelly, R |
| collection | OXFORD |
| description | 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-beta, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. Combined before BMT KGF + PFT-beta 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-beta 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. |
| first_indexed | 2024-03-07T05:25:14Z |
| format | Journal article |
| id | oxford-uuid:e050843f-733a-4028-9ccb-977802b5ebe7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:25:14Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:e050843f-733a-4028-9ccb-977802b5ebe72022-03-27T09:46:22ZShort-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e050843f-733a-4028-9ccb-977802b5ebe7EnglishSymplectic Elements at Oxford2010Kelly, RGoren, ETaylor, PMueller, SNStefanski, HOsborn, MScott, HKomarova, EGudkov, AHolländer, GBlazar, BMyeloablative 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-beta, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. Combined before BMT KGF + PFT-beta 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-beta 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. |
| spellingShingle | Kelly, R Goren, E Taylor, P Mueller, SN Stefanski, H Osborn, M Scott, H Komarova, E Gudkov, A Holländer, G Blazar, B 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. |
| 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| work_keys_str_mv | AT kellyr shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT gorene shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT taylorp shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT muellersn shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT stefanskih shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT osbornm shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT scotth shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT komarovae shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT gudkova shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT hollanderg shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation AT blazarb shortterminhibitionofp53combinedwithkeratinocytegrowthfactorimprovesthymicepithelialcellrecoveryandenhancestcellreconstitutionaftermurinebonemarrowtransplantation |