Abstract
T cell immunodeficiency is a major complication of bone marrow (BM) transplantation (BMT). Therefore, approaches to enhance T cell reconstitution after BMT are required. We have purified a hybrid cytokine, consisting of IL-7 and the β-chain of hepatocyte growth factor (HGFβ) (IL-7/HGFβ), from a unique long-term BM culture system. We have cloned and expressed the IL-7/HGFβ gene in which the IL-7 and HGFβ genes are connected by a flexible linker to generate rIL-7/HGFβ protein. Here, we show that rIL-7/HGFβ treatment enhances thymopoiesis after allogeneic BMT. Although rIL-7 treatment also enhances the number of thymocytes, rIL-7/HGFβ hybrid cytokine was more effective than was rIL-7 and the mechanisms by which rIL-7 and rIL-7/HGFβ increase the numbers of thymocytes are different. rIL-7 enhances the survival of double negative (DN), CD4 and CD8 single positive (SP) thymocytes. In contrast, rIL-7/HGFβ enhances the proliferation of the DN, SP thymocytes, as well as the survival of CD4 and CD8 double positive (DP) thymocytes. rIL-7/HGFβ treatment also increases the numbers of early thymocyte progenitors (ETPs) and thymic epithelial cells (TECs). The enhanced thymic reconstitution in the rIL-7/HGFβ-treated allogeneic BMT recipients results in increased number and functional activities of peripheral T cells. Graft-versus-host-disease (GVHD) is not induced in the rIL-7/HGFβ-treated BMT mice. Therefore, rIL-7/HGFβ may offer a new tool for the prevention and/or treatment of T cell immunodeficiency following BMT.
Highlights
BMT, the most common cell-based therapy applied today, is widely used in the treatment of cancer, aplastic anemia, and primary and secondary immunodeficiency disorders
The mechanisms by which rIL-7 and rIL-7/HGFβ increase the numbers of thymocytes are different. rIL-7 enhances the survival of double negative (DN) and single positive (SP) thymocytes by enhancing the expression of Bcl-2, whereas rIL-7/HGFβ induces the proliferation of these cells. rIL-7/HGFβ enhances the survival of pre-selection double positive (DP) thymocytes, at least in part, by increasing the expression of Bcl-xL
The mechanisms by which rIL-7 and rIL-7/HGFβ enhance thymopoiesis are different. rIL-7 enhances the survival of DN and SP thymocytes, whereas rIL-7/HGFβ enhances the survival of DP thymocytes, and the proliferation of DN, CD4 and CD8 SP thymocytes. rIL-7/HGFβ treatment significantly increases the numbers of early thymocyte progenitors (ETPs) and thymic epithelial cells (TECs), whereas rIL-7 does not
Summary
BMT, the most common cell-based therapy applied today, is widely used in the treatment of cancer, aplastic anemia, and primary and secondary immunodeficiency disorders. We previously reported that in vivo administration of rIL-7/HGFβ significantly enhances thymopoiesis after syngeneic BMT, resulting in increased numbers of total and naïve T cells in the periphery of the recipients [8]. RIL-7 enhances the survival of DN and SP thymocytes by enhancing the expression of Bcl-2, whereas rIL-7/HGFβ induces the proliferation of these cells. RIL-7/HGFβ enhances the survival of pre-selection DP thymocytes, at least in part, by increasing the expression of Bcl-xL. RIL-7/HGFβ increases the number of ETPs and TECs. The enhanced thymopoiesis in the rIL-7/HGFβ-treated allo-BMT recipients resulted in increased numbers of T cells in the periphery. The functions of peripheral T cells in the rIL-7/HGFβ-treated allo-BMT recipients were rapidly restored, but GVHD was not induced. RIL-7/HGFβ may offer a new approach to preventing and/or correcting T cell deficiency post-BMT
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