Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease.
Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6(-/-) mice received allogeneic non-T cell-depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6(-/-) recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6(-/-) recipients' liver. When mice received 0.5 x 10(6) allogeneic T cells with T cell-depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6(-/-) than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6(-/-) T-cell proliferation. We therefore assessed the response of WT or Gas6(-/-) ECs to tumor necrosis factor-alpha. Lymphocyte transmigration was less extensive through Gas6(-/-) than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.
Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Laurent
L
Burnier
François
F
Saller
Linda
L
Kadi
Anne C
AC
Brisset
Rocco
R
Sugamele
Lucie
L
Baudino
Françoise
F
Bono
Jean-Marc
JM
Herbert
Peter
P
Carmeliet
Marc
M
Schapira
Shozo
S
Izui
Anne
A
Angelillo-Scherrer
D000818:Animals; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D000099255:Growth Arrest-Specific Protein 6