Keratinocyte growth factor improves allogeneic bone marrow engraftment through a CD4+Foxp3+ regulatory T cell-dependent mechanism.
Keratinocyte growth factor (KGF) protects mice from acute graft-vs-host disease and graft rejection by cytoprotective and yet incompletely understood immunological mechanisms. Recently, we showed that administration of KGF induces selective peripheral expansion of CD4(+)Foxp3(+) regulatory T cells (Treg). In this study, we set out to assess whether the peripheral expansion of Treg accounts for the immunomodulatory effects of KGF after bone marrow (BM) transplantation. To exclude potentially confounding cytoprotective and thymopoietic effects of KGF, we applied KGF to congenic wild-type mice that served as T cell provider mice for T and B cell-deficient RAG-1(-/-) mice that were subsequently transplanted with allogeneic BM. Treatment of congenic T cell provider mice with KGF significantly improved engraftment and reduced graft rejection in BMT recipients. CD4(+)Foxp3(+) Treg remained increased for 4 wk, while expansion of congenic CD3(+) T cells was inhibited. To assess a causal relationship between expansion of Treg and improved BM engraftment, congenic Scurfy mice, which lack Foxp3(+) Treg, served as T cell provider mice and were treated with KGF. KGF-treatment of Scurfy mice did not affect engraftment nor did it inhibit the expansion of congenic T cells. These data demonstrate that administration of KGF to the T cell provider mice improves engraftment of allogeneic BM through a CD4(+)Foxp3(+) Treg-dependent mechanism.
Bruinsma
Marieke
M
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
van Soest
Peter L
PL
Leenen
Pieter J M
PJ
Löwenberg
Bob
B
Cornelissen
Jan J
JJ
Braakman
Eric
E
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology*; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051523:Fibroblast Growth Factor 7