scholarly journals Keratinocyte Growth Factor Improves Allogeneic Bone Marrow Engraftment through a CD4+Foxp3+Regulatory T Cell-Dependent Mechanism

2009 ◽  
Vol 182 (12) ◽  
pp. 7364-7369 ◽  
Author(s):  
Marieke Bruinsma ◽  
Peter L. van Soest ◽  
Pieter J. M. Leenen ◽  
Bob Löwenberg ◽  
Jan J. Cornelissen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Growth Factor ◽  
Regulatory T Cell ◽  
Keratinocyte Growth Factor ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Bone Marrow Engraftment ◽  
Dependent Mechanism

Keratinocyte Growth Factor Increases the CD4+Foxp3+ Regulatory T Cell-Pool by an Early Thymus-Independent and a Late Thymus-Dependent Mechanism.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3211-3211
Author(s):  
Marieke Bruinsma ◽  
Peter L. van Soest ◽  
Pieter J.M. Leenen ◽  
Bob Lowenberg ◽  
Jan J. Cornelissen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Regulatory T Cell ◽  
Graft Rejection ◽  
Keratinocyte Growth Factor ◽  
Marrow Graft ◽  
Cell Numbers ◽  
Dependent Mechanism

Abstract Administration of keratinocyte growth factor (KGF) before and shortly after experimental allogeneic bone marrow transplantation (allo-BMT) has been shown to reduce the incidence and severity of graft versus host disease (GVHD) and to inhibit graft rejection. As naturally occurring CD4+Foxp3+ regulatory T cells (Treg) play an important role in the prevention of GVHD and graft rejection, we evaluated the effect of KGF on peripheral and thymic CD4+Foxp3+ regulatory T cell numbers in normal mice and BMT recipients. KGF (5mg/kg/day) was administered subcutaneously to adult B6 mice for 3 consecutive days. KGF enhanced the frequency of CD4+Foxp3+ Treg in peripheral blood and spleen twofold, to more than 15 % of CD4+ T cells, resulting in an increase in absolute numbers of CD4+Foxp3+ Treg within one week. From 2 weeks onwards, the frequency of CD4+Foxp3+ Treg gradually normalized, but the absolute numbers of Treg remained elevated (> 10 weeks) due to an increase of both CD4 and CD8 T cell numbers. In order to assess the relative contribution of thymic output versus peripherally expanded Treg, we next determined the frequency of T-cell receptor excision circles (TREC) in peripheral blood T cells. Analysis of sorted CD4+Foxp3+ Treg and CD4+Foxp3− conventional T cells showed a decline in TREC frequency in both subsets 1 week after KGF administration, suggesting peripheral expansion. In contrast, the TREC frequency in peripheral T cells was significantly higher at 5 and 10 weeks after KGF, indicating a late thymic dependent effect. Normal B6 mice that were adoptively transferred with congenic T cells showed an enhanced, but transient, increase of the frequency of CD4+Foxp3+ Treg within one week, also suggesting that the early effect of KGF on peripheral Treg is independent of thymic output. In addition, we assessed the effects of KGF on Foxp3+ thymocytes. Thymic weight and thymic cellularity of all subsets, including CD4+Foxp3+ thymocytes, were 2 to 3-fold increased one week after KGF administration as compared to control mice. In addition, we found that KGF transiently affected the thymic architecture. The medullary epithelial compartment was virtually absent one week after KGF administration. Normal thymic architecture gradually reappeared after 2–3 weeks. To determine whether KGF-enhanced Treg numbers in BMT recipients would inhibit graft rejection, KGF was administered from day -3 until day -1 to Rag-1−/− mice. Subsequently, the mice were 3Gy irradiated, supplied with 105 B6 CD45.1 congenic T cells and transplanted with a MHC-matched minor-Ag mismatched T cell depleted 129Sv bone marrow graft. As in normal B6 mice, KGF-treatment of BMT-recipients enhanced peripheral CD45.1+CD4+Foxp3+ Treg numbers. This was associated with a reduced rate of bone marrow graft rejection (2 out of 8 KGF-treated mice as compared to 5 out of 7 PBS-treated mice). Taken together, our data show that KGF enhances the peripheral Treg pool by an early, transient and selective thymus-independent mechanism and thereafter by a non-selective thymus-dependent mechanism. The KGF-mediated expansion of the pool of peripheral Treg may contribute to the inhibitory effects of KGF on graft rejection.

scholarly journals Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2453-2460 ◽  
Author(s):  
Önder Alpdogan ◽  
Vanessa M. Hubbard ◽  
Odette M. Smith ◽  
Neel Patel ◽  
Sydney Lu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Critical Role ◽  
T Cell Development ◽  
Marrow Transplant ◽  
Cell Development ◽  
Allogeneic Bone ◽  
Thymic Regeneration

AbstractKeratinocyte growth factor (KGF) is a member of the fibroblast growth factor family that mediates epithelial cell proliferation and differentiation in a variety of tissues, including the thymus. We studied the role of KGF in T-cell development with KGF-/- mice and demonstrated that thymic cellularity and the distribution of thymocyte subsets among KGF-/-, wildtype (WT), and KGF+/- mice were similar. However, KGF-/- mice are more vulnerable to sublethal irradiation (450 cGy), and a significant decrease was found in thymic cellularity after irradiation. Defective thymopoiesis and peripheral T-cell reconstitution were found in KGF-/- recipients of syngeneic or allogeneic bone marrow transplant, but using KGF-/- mice as a donor did not affect T-cell development after transplantation. Despite causing an early developmental block in the thymus, administration of KGF to young and old mice enhanced thymopoiesis. Exogenous KGF also accelerated thymic recovery after irradiation, cyclophosphamide, and dexamethasone treatment. Finally, we found that administering KGF before bone marrow transplantation (BMT) resulted in enhanced thymopoiesis and peripheral T-cell numbers in middle-aged recipients of an allogeneic BM transplant. We conclude that KGF plays a critical role in postnatal thymic regeneration and may be useful in treating immune deficiency conditions. (Blood. 2006;107:2453-2460)

scholarly journals Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5734-5744 ◽  
Author(s):  
Ryan M. Kelly ◽  
Steven L. Highfill ◽  
Angela Panoskaltsis-Mortari ◽  
Patricia A. Taylor ◽  
Richard L. Boyd ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Combined Treatment ◽  
Leuprolide Acetate ◽  
Allogeneic Bone ◽  
Individual Agent ◽  
T Cell Reconstitution ◽  
Androgen Blockade

Abstract Myeloablative conditioning results in thymic epithelial cell (TEC) injury, slow T-cell reconstitution, and a high risk of opportunistic infections. Keratinocyte growth factor (KGF) stimulates TEC proliferation and, when given preconditioning, reduces TEC injury. Thymocytes and TECs express androgen receptors, and exposure to androgen inhibits thymopoiesis. In this study, we have investigated whether TEC stimulation via preconditioning treatment with KGF and leuprolide acetate (Lupron), 2 clinically approved agents, given only before conditioning would circumvent the profound TEC and associated T-cell deficiency seen in allogeneic bone marrow transplant (BMT) recipients. Only combined treatment with KGF plus leuprolide acetate normalized TEC subset numbers and thymic architecture. Thymopoiesis and thymic output were supranormal, leading to the accelerated peripheral reconstitution of naive CD4 and CD8 T cells with a broad Vβ repertoire and decreased homeostatic T-cell proliferation. Combined therapy facilitated T:B cooperativity and enabled a B-cell humoral response to a CD4 T cell–dependent neoantigen challenge soon after BMT. In vivo antigen-specific CD8 T-cell responses and clearance of a live pathogen was superior with combined versus individual agent therapy. Thus, KGF combined with androgen blockade represents a novel approach to restore thymic function and facilitates the rapid recovery of peripheral T-cell function after allogeneic BMT.

scholarly journals Regulatory T Cell Reconstitution is Delayed Following Allogeneic Bone Marrow Transplantation

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Gabrielle L Goldberg ◽  
Rebecca H Ajodan ◽  
Robert M Samstein ◽  
David Y Suh ◽  
Christopher G King ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Regulatory T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
T Cell Reconstitution
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