Keratinocyte growth factor (KGF) is one of several cytokines that induce epithelial cell growth and differentiation, and it has recently been found to help prevent mucositis following high-dose chemotherapy. In this paper, Alpdogan and colleagues show that KGF also improves T-cell production in mice whose normal thymic function has been impaired by either irradiation or by aging. T-cell production in the thymus declines dramatically after childhood and is also compromised following allogeneic stem cell transplantation (SCT). Older recipients of SCT have the most impaired thymopoiesis, leading directly to both immunodeficiency and worsened graft-versus-host disease in adult recipients of allo-SCT, which together comprise the major barriers to safe allo-SCT. If one could amelerioate or prevent thymic dysfunction following SCT, patients would have far fewer infections, and almost certainly much reduced GVHD as well, resulting in much improved survival. In this paper, the authors began by studying T-cell production in mice genetically engineered to lack KGF. Under normal, gentle conditions, T cells developed normally in these mice. If, however, the mice were treated with high doses of irradiation or cyclophosphamide, de novo T-cell production through the thymus was impaired in these KGF-/- mice, compared with the recovery of normal mice. This defect in KGF-/- mice was not due to a stem cell defect, but to the non-stem cell microenvironment caused by the KGF deficiency. Finally, the administration of recombinant KGF corrected this defect, thus "closing the loop" to demonstrate that KGF deficiency will lead to non-stem cell dysfunction which prevents normal stem cells from developing into functional T cells. To test whether administering pharmacologic KGF could be applied to the clinic, the authors tested the effects of KGF on normal mice, both at baseline and following XRT, chemotherapy +/- allogeneic transplantation. They found that KGF enhanced T-cell production in normal young and old mice and significantly improved recovery following sublethal XRT or chemotherapy. Most interestingly, KGF increased thymopoiesis in normal middle-aged mice, but the effect was actually not apparent until two to three months following transplantation.
In Brief
Taken together, these very promising studies point the way to clinical trials of KGF for the prevention of T-cell immunodeficiency, particularly in the setting of stem cell transplantation. Just as G-CSF and Epo have proven to be extremely useful molecular pharmaceuticals for hematopoietic cells over the past two decades, KGF may prove to be the first effective stromal cell stimulant in the years to come. Let the careful trials begin.
Competing Interests
Dr. Emerson indicated no relevant conflicts of interest.
