In Vivo Administration of the Recombinant IL-7/Hepatocyte Growth Factor β Hybrid Cytokine Efficiently Restores Thymopoiesis and Naive T Cell Generation in Lethally Irradiated Mice after Syngeneic Bone Marrow Transplantation

Abstract

Bone marrow transplantation (BMT) is often followed by a prolonged period of T cell deficiency. Therefore, the enhancement of T cell reconstitution is an important clinical goal. We have identified a novel hybrid cytokine containing IL-7 and the β-chain of hepatocyte growth factor (HGF) in the supernatant of cultured mouse BM stromal cells. We have cloned and expressed the IL-7/HGFβ gene to produce a single-chain rIL-7/HGFβ protein that stimulates the in vitro proliferation of thymocytes, early B-lineage cell, and day 12 spleen CFUs. In this study, we show that, following syngenic BMT, the in vivo administration of rIL-7/HGFβ supports the rapid and complete regeneration of the thymus and efficiently reconstitutes the pool of naive T cells having a normally diverse TCR repertoire. The rIL-7/HGFβ hybrid cytokine was significantly more effective quantitatively than was rIL-7 and differed qualitatively in its ability to cross-link c-Met and IL-7Rα and to stimulate the expansion of early thymocyte progenitors and thymic epithelial cells. It also supports the maturation and homeostatic expansion of peripheral T cells. Consequently, the in vivo administration of rIL-7/HGFβ may offer a new approach to preventing and/or correcting post-BMT T cell immune deficiency.