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Keratinocyte Growth Factor Improves Allogeneic Bone Marrow Engraftment through a CD4⁺Foxp3⁺ Regulatory T Cell-Dependent Mechanism¹

Marieke Bruinsma^*, Peter L. van Soest^*, Pieter J. M. Leenen, Bob Löwenberg^*, Jan J. Cornelissen^* and Eric Braakman^2,*

^* Department of Hematology, Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was in part supported by the Landsteiner Foundation for Blood Transfusion Research (Grant No. 0221).

² Address correspondence and reprint requests to Dr. Eric Braakman, Erasmus University Medical Center, Department of Hematology, Dr. Molewaterplein 50, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: e.braakman{at}erasmusmc.nl

³ Abbreviations used in this paper: KGF, keratinocyte growth factor; allo-BMT, allogeneic bone marrow transplantation; GVHD, graft-vs-host disease; Treg, regulatory T cell; WT, wild type; BM, bone marrow; BMT, bone marrow transplantation.