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. 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.
Kelly
Ryan M
RM
Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
Goren
Emily M
EM
Taylor
Patricia A
PA
Mueller
Scott N
SN
Stefanski
Heather E
HE
Osborn
Mark J
MJ
Scott
Hamish S
HS
Komarova
Elena A
EA
Gudkov
Andrei V
AV
Holländer
Georg A
GA
Blazar
Bruce R
BR
D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D052160:Benzothiazoles / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D054421:Chemokine CCL21 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D008089:Listeria monocytogenes / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D052160:Benzothiazoles; D054421:Chemokine CCL21; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051523:Fibroblast Growth Factor 7; D014050:Toluene; C121565:pifithrin