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CD4⁺ T Cells Generated De Novo from Donor Hemopoietic Stem Cells Mediate the Evolution from Acute to Chronic Graft-versus-Host Disease¹

Yi Zhang^*, Elizabeth Hexner^*, Dale Frank and Stephen G. Emerson^2,*

^* Department of Medicine and Pediatrics and Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Acute and chronic graft-versus-host disease (GVHD) remain the major complications limiting the efficacy of allogeneic hemopoietic stem cell transplantation. Chronic GVHD can evolve from acute GVHD, or in some cases may overlap with acute GVHD, but how acute GVHD evolves to chronic GVHD is unknown. In this study, in a classical CD8⁺ T cell-dependent mouse model, we found that pathogenic donor CD4⁺ T cells developed from engrafted hemopoietic stem cells (HSCs) in C57BL/6SJL(B6/SJL, H-2^b) mice suffering from acute GVHD after receiving donor CD8⁺ T cells and HSCs from C3H.SW mice (H-2^b). These CD4⁺ T cells were activated, infiltrated into GVHD target tissues, and produced high levels of IFN-. These in vivo-generated CD4⁺ T cells caused lesions characteristic of chronic GVHD when adoptively transferred into secondary allogeneic recipients and also caused GVHD when administered into autologous C3H.SW recipients. The in vivo generation of pathogenic CD4⁺ T cells from engrafted donor HSCs was thymopoiesis dependent. Keratinocyte growth factor treatment improved the reconstitution of recipient thymic dendritic cells in CD8⁺ T cell-repleted allogeneic hemopoietic stem cell transplantation and prevented the development of pathogenic donor CD4⁺ T cells. These results suggest that de novo-generated donor CD4⁺ T cells, arising during acute graft-versus-host reactions, are key contributors to the evolution from acute to chronic GVHD. Preventing or limiting thymic damage may directly ameliorate chronic GVHD.

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 supported by a grant of the Specialized Center for Research from the Leukemia and Lymphoma Society of America and Grant R01 CA102464-01 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Stephen G. Emerson, Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. E-mail address: emersons{at}mail.med.upenn.edu

³ Abbreviations used in this paper: GVHD, graft-versus-host disease; allo-HSCT, allogeneic hemopoietic stem cell transplantation; HSC, hemopoietic stem cell; GVH, graft-versus-host; miHA, minor histocompatibility Ag; KGF, keratinocyte growth factor; DC, dendritic cell; BMT, bone marrow transplant; BM, bone marrow; TCD, T cell depleted; DP, double positive; SP, single positive; MHC-II, MHC class II; T_reg, regulatory T cell; Flt3L, Flt3 ligand.

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