RESUMO
BACKGROUND: T-cell regeneration after bone marrow transplantation (BMT) is often slow and incomplete. Therefore, the enhancement of T-cell reconstitution after BMT is required. We have previously described a naturally occurring hybrid cytokine consisting of interleukin (IL)-7 and the ß-chain of hepatocyte growth factor (HGF) that had lymphopoietic stimulatory activity in vitro. We have also reported that a murine recombinant (r) IL-7/HGFß protein significantly enhances T-cell regeneration in mice after BMT. METHODS: To determine whether a human form of rIL-7/HGFß has similar effects as the murine form, we have cloned and expressed the human IL-7 and HGFß genes to produce a single-chain hrIL-7/HGFß protein. We have also cloned and expressed a human form of hybrid cytokine containing IL-7 and the α-chain of HGF (HGFα) (hrIL-7/HGFα). We then determined their ability to enhance T-cell reconstitution in mice after BMT. RESULTS: We found that hrIL-7/HGFα had higher in vitro and in vivo thymocyte-stimulatory activities than did the hrIL-7/HGFß. Therefore, we focused on the functional properties of hrIL-7/HGFα and showed that administration of hrIL-7/HGFα significantly enhanced thymopoiesis in mice after syngeneic BMT by increasing the numbers of thymocytes, early thymocyte progenitors, and thymic epithelial cells. hrIL-7/HGFα cross-linked the IL-7 and HGF receptors on thymocytes, and the in vivo thymocyte-stimulatory activity was mediated by both receptors. Consequently, hrIL-7/HGFα treatment significantly increased the numbers of total and naïve T cells in the periphery. CONCLUSION: In vivo administration of hrIL-7/HGFα efficiently restores thymopoiesis and naïve T-cell reconstitution in mice after syngeneic BMT.
