| Decreased thymopoietic capacity contributes to the severe and clinically significant immune deficiency seen after irradiation, chemotherapy hematopoietic stem cell transplantation (HSCT). The ability of adults to reconstitute the T cell compartment after damage is interfered by aging. Thymic insufficiency is associated with impaired intrathymic production of IL-7 by thymic epithelial cells (TEC), possibly the loss of the IL-7-producing TEC, which can be partially treated by 1L-7 administration. It has been known that administration of keratinocyte growth factor (KGF, or Fgf7), an epithelial cell-specific growth factor, protects mucosal, cutaneous, and pulmonary epithelial cells from cytotoxic therapy-induced damage. Thus, we hypothesized that KGF treatment would improve thymic function by protecting TEC from damage or inducing TEC proliferation. A single 3-day course of KGF treatment improved thymopoiesis hampered by pre-HSCT conditioning, GVDH and aging, enhanced thymopoiesis by KGF was maintained for at least 2 months in each model. KGF increased numbers of TEC and intrathymic IL-7 production, and the observed effect of KGF required an intact IL7 signaling pathway. KGF treatment caused increased numbers of naive CD4+ T cells and total mature T cells, indicating that the increased T cell numbers resulted from enhanced thymopoiesis rather than only peripheral expansion of memory T cells. KGF treatment also enhanced T-cell dependent antibody production in response to vaccination. The ability of KGF to increase thymopoiesis and immune responsiveness suggests that TEC damage is pathophysiologically important in thymic insufficiency, and KGF may be therapeutically useful in maintenance of thymopoiesis in HSCT recipients or aged individuals. |
