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Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Saller, François
Kadi, Linda
Brisset, A. C.
Sugamele, Rocco
Bono, Françoise
Herbert, J. M.
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Published in Blood. 2010, vol. 115, no. 16, p. 3390-3397
Abstract 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.
Keywords AnimalsCell SeparationChemotaxis, Leukocyte/genetics/immunologyEndothelial Cells/metabolismFlow CytometryGraft vs Host Disease/genetics/immunology/*prevention & controlHematopoietic Stem Cell Transplantation/*adverse effectsImmunohistochemistryIntercellular Signaling Peptides and Proteins/*deficiency/geneticsLiver/*immunology/pathologyLymphocyte Activation/immunologyLymphocyte Culture Test, MixedMiceMice, KnockoutReverse Transcriptase Polymerase Chain ReactionT-Lymphocytes/cytology/immunology/metabolismTransplantation, Homologous
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PMID: 20139094
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