期刊
BLOOD
卷 115, 期 5, 页码 1088-1097出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-05-223198
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资金
- National Institutes of Health [R01-HL073794, R01-HL55209, R01-A1057477-01, R01A1057477-01, R01-CA75179, P01CA067493]
- Swiss National Science Foundation (SNF) [3100-68310.02]
- Children's Cancer Research Fund (CCRF)
- European Community
- National Center for Research Resources (NCRR) Shared Instrumentation [1 S10 RR16851]
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. (Blood. 2010;115:1088-1097)
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