scholarly journals 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

Blood ◽  
2010 ◽  
Vol 115 (5) ◽  
pp. 1088-1097 ◽  
Author(s):  
Ryan M. Kelly ◽  
Emily M. Goren ◽  
Patricia A. Taylor ◽  
Scott N. Mueller ◽  
Heather E. Stefanski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Marrow Transplantation ◽  
Keratinocyte Growth Factor ◽  
Thymic Epithelial Cell ◽  
Cell Recovery ◽  
T Cell Reconstitution

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.

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.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4485-4485
Author(s):  
Ryan Kelly ◽  
Emily Goren ◽  
Patricia Taylor ◽  
Hamish S Scott ◽  
Elena Komarova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Marrow Transplantation ◽  
Keratinocyte Growth Factor ◽  
Thymic Epithelial Cell ◽  
Cell Recovery ◽  
T Cell Reconstitution

Abstract Abstract 4485 Myeloablative conditioning prior to 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 following BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given prior to conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BMT recipients. Therefore, we investigated whether the addition of a pharmacological inhibitor, PFT-β to transiently inhibit p53 during radiotherapy could spare TEC from radiation-induced damage in congenic and allogeneic BMT. The combined pre-BMT administration of KGF plus PFT-β additively restored numbers of cortical and medullary TEC and improved thymic function post-BMT, resulting in higher numbers of donor-derived, naïve peripheral CD4+ and CD8+ T-cells. Improved T-cell reconstitution correlated with enhanced recovery of fibroblastic reticular cells in the lymph node stromal compartment, and a superior immune response against L. 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 following BMT. Disclosures: No relevant conflicts of interest to declare.

Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4592-4600 ◽  
Author(s):  
Dullei Min ◽  
Patricia A. Taylor ◽  
Angela Panoskaltsis-Mortari ◽  
Brile Chung ◽  
Dimitry M. Danilenko ◽  
...  
Keyword(s):  
Immune Deficiency ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Marrow Transplantation ◽  
Keratinocyte Growth Factor ◽  
Thymic Epithelial Cells ◽  
Thymic Epithelial Cell

Decreased thymopoietic capacity contributes to the severe and clinically significant immune deficiency seen after bone marrow transplantation (BMT). One mechanism for thymopoietic failure is damage to the interleukin 7 (IL-7)–producing thymic epithelial cells (TECs) by irradiation and chemotherapy, which can be partially treated by IL-7 administration. Pretreatment of BMT recipients with keratinocyte growth factor (KGF, or Fgf7), an epithelial cell–specific growth factor, protects mucosal, cutaneous, and pulmonary epithelial cells from cytotoxic therapy-induced damage in experimental murine models. Like other epithelial cells, TECs specifically express KGF receptors. Because KGF specifically protects KGF receptor–bearing epithelial cells and post-BMT immune deficiency is caused by loss of TECs, we hypothesized that KGF pretreatment would improve post-BMT thymic function. To test the hypothesis, BMT recipient mice were given KGF or placebo prior to congenic or allogeneic BMT. Administration of KGF before murine BMT significantly increased the capacity of the thymus to generate donor-derived thymocytes. KGF pretreatment also normalized the proportion of thymic subpopulations, increased the number of naive T cells in the periphery, and improved the response to neoantigen immunization. KGF treatment caused increased production of intrathymic IL-7, and the thymopoietic effects of KGF required an intact IL-7 signaling pathway. These results demonstrate that KGF may have immunomodulatory effects by a unique mechanism of protection of TECs. Furthermore, thymic injury and prolonged posttransplantation immune deficiency in BMT recipients can be prevented by KGF administration.

Keratinocyte Growth Factor (KGF) Is Required for Post-Natal Thymic Regeneration.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1231-1231
Author(s):  
Onder Alpdogan ◽  
Vanessa M. Hubbard ◽  
Stephanie J. Muriglan ◽  
Adam A. Kochman ◽  
Jeffrey M. Eng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Marrow Transplantation ◽  
Thymic Epithelial Cells ◽  
Allogeneic Bone ◽  
Allogeneic Bmt ◽  
Thymic Regeneration

Abstract KGF is a fibroblast growth factor family member (FGF-7) that mediates epithelial cell proliferation and differentiation in a variety of tissues, including thymic epithelial cells. Recent studies have demonstrated that KGF administration (before conditioning) to the recipients of allogeneic bone marrow transplantation (BMT) can enhance T cell and thymic reconstitution. Therefore, we studied the role of KGF on T cell development under normal and stress conditions (such as irradiation) by using KGF (−/−) mice in experimental murine models. Phenotypic analysis of KGF (−/−) mice at varying ages demonstrated that the bone marrow, thymus and lymph node cellularity and the cell distribution among KGF (−/−), wild type (WT) and KGF (+/−) mice (6–11 weeks of age) were similar. However, splenic cellularity and splenic T cell numbers were slightly lower than WT and littermate controls. KGF (−/−) mice are more vulnerable to sublethal irradiation (450–600 cGy) and a more than six fold decrease was found in thymic cellularity when analyzed on day 28 after irradiation, whereas there was no delay in the erythroid, myeloid and platelet recovery after irradiation. We used bone marrow transplantation models to assess the relative contribution of KGF produced by thymocytes or thymic epithelial cells during thymic regeneration after irradiation. T cell reconstitution was impaired in syngeneic or allogeneic KGF (−/−) BMT recipients in comparison to littermate controls but there was no difference in the distribution of thymocyte subsets or splenic T cell content. The recipients of KGF (−/−) bone marrow had decreased thymic and splenic cellularity after allogeneic BMT. These data demonstrate that both donor and host derived KGF play a role in thymic regeneration. Finally, KGF administration to young and old mice (10 month old) enhanced thymopoiesis when analyzed 28 days after KGF administration. Pre-BMT KGF administration to the recipients of syngeneic and allogeneic BMT also resulted in a 2–6 fold increase in the thymic cellularity compared to the control group. We conclude that KGF produced by both thymocytes and epithelial cells is not required for normal and post-natal thymic development, but plays a role in post-natal thymic regeneration after irradiation. These data support the potential use of KGF to protect or restore thymic damage after chemo/radiotherapy.

Efficacy and Costs of Granulocyte Colony-Stimulating Factor in Allogeneic T-Cell Depleted Bone Marrow Transplantation

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2725-2729 ◽  
Author(s):  
Stephanie J. Lee ◽  
Edie Weller ◽  
Edwin P. Alyea ◽  
Jerome Ritz ◽  
Robert J. Soiffer
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Growth Factor ◽  
Marrow Transplantation ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Marrow Infusion ◽  
Stimulating Factor

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P < .0001) and time from marrow infusion to discharge (23 days v 17 days,P < .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs. © 1998 by The American Society of Hematology.

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