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Blood, 15 June 2002, Vol. 99, No. 12, pp. 4592-4600
TRANSPLANTATION
Protection from thymic epithelial cell injury by keratinocyte
growth factor: a new approach to improve thymic and peripheral T-cell
reconstitution after bone marrow transplantation
Dullei Min,
Patricia A. Taylor,
Angela Panoskaltsis-Mortari,
Brile Chung,
Dimitry M. Danilenko,
Catherine Farrell,
David L. Lacey,
Bruce R. Blazar, and
Kenneth I. Weinberg
From the Division of Research Immunology/BMT, Childrens
Hospital Los Angeles, CA; the Division of Pediatric Bone Marrow
Transplantation and the Cancer Center, University of Minnesota,
Minneapolis, MN; and Amgen, Thousand Oaks, CA.
Decreased thymopoietic capacity contributes to the severe and
clinically significant immune deficiency seen after bone marrow transplantation (BMT). One mechanism for thymopoietic failure is damage
to the interleukin 7 (IL-7)-producing thymic epithelial cells (TECs)
by irradiation and chemotherapy, which can be partially treated by IL-7
administration. Pretreatment of BMT recipients with keratinocyte growth
factor (KGF, or Fgf7), an epithelial cell-specific growth factor,
protects mucosal, cutaneous, and pulmonary epithelial cells from
cytotoxic therapy-induced damage in experimental murine models. Like
other epithelial cells, TECs specifically express KGF receptors.
Because KGF specifically protects KGF receptor-bearing epithelial
cells and post-BMT immune deficiency is caused by loss of TECs, we
hypothesized that KGF pretreatment would improve post-BMT thymic
function. To test the hypothesis, BMT recipient mice were given KGF or
placebo prior to congenic or allogeneic BMT. Administration of KGF
before murine BMT significantly increased the capacity of the thymus to
generate donor-derived thymocytes. KGF pretreatment also normalized the
proportion of thymic subpopulations, increased the number of naive T
cells in the periphery, and improved the response to neoantigen
immunization. KGF treatment caused increased production of intrathymic
IL-7, and the thymopoietic effects of KGF required an intact IL-7
signaling pathway. These results demonstrate that KGF may have
immunomodulatory effects by a unique mechanism of protection of TECs.
Furthermore, thymic injury and prolonged posttransplantation immune
deficiency in BMT recipients can be prevented by KGF administration.
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