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-, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs.
IntroductionAllogeneic bone marrow transplantation (BMT) is used to treat malignant and nonmalignant disorders. 1,2 Chemoradiotherapy conditioning preceding donor graft infusion damages thymic stroma, severely delaying peripheral CD4 ϩ and CD8 ϩ T-cell reconstitution. [2][3][4][5][6] Thus, BM transplant recipients are at increased risk of opportunistic fungal and viral infections. 7 Thymic stroma is composed of a 3-dimensional matrix of thymic epithelial cells (TECs), fibroblasts, macrophages, dendritic cells (DCs), and mesenchymal cells. 8 Critical signals are supplied by TECs to developing thymocytes directing their thymic ingress, 9,10 survival, 11,12 trafficking, 11 selection, 13 and export. 11 Conditioning depletes TECs, impairing T-cell production for prolonged periods of time after BMT. [14][15][16][17] Restoring thymic function would speed peripheral T-cell recovery after BMT.Developing thymocytes can be distinguished by their CD4 and CD8 cell surface expression. CD4 Ϫ CD8 Ϫ (double-negative, DN) thymocytes mature to become CD4 ϩ CD8 ϩ (double-positive, DP) thymocytes and undergo positive selection on cortical TECs (cTECs). DP thymocytes continue their maturation into CD4 ϩ or CD8 ϩ (single-positive, SP) thymocytes and migrate into the thymic medulla where negative selection is mediated by medullary TECs (mTECs) and medullary DCs. 8 SP thymocytes complete their maturation in the medulla and are exported into the periphery as mature T cells. 13 Keratinocyte growth factor (KGF) is a fibroblast growth factor family member that controls cell migration, proliferation, and differentiation in epithelial tissues. 18 Endogenous KGF is upregulated in mucosal tissues after injury, and exogenous KGF enhances protection/repair of epithelial cells in models of chemoradiotherapy-induced injury. 18 KGF is approved by the Food and Drug Administration for prevention of oral mucositis associated with high-dose chemoradiotherapy and hematopoietic stem cell transplantation. [19][20][21] KGF is produced by thymic mesenchymal cells and binds exclusively to FGFR2-IIIb expressed by TECs. 15,22 KGF is a potent mitogen for TECs. 23 KGF pretreatment prevents thymic injury and prolonged T-cell deficiency in murine BMT models. 15,[23][24][25][26][27] KGF facilitates alloe...