title: Promoting regulation via the inhibition of DNAM-1 after transplantation.
abstract: Donor T cells play pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects following bone marrow transplantation (BMT). DNAX accessory molecule 1 (DNAM-1) is a costimulatory and adhesion molecule, expressed mainly by natural killer cells and CD8(+) T cells at steady state to promote adhesion to ligand-expressing targets and enhance cytolysis. We have analyzed the role of this pathway in GVHD and GVL. The absence of DNAM-1 on the donor graft attenuated GVHD in major histocompatibility complex (MHC)-mismatched and MHC-matched BMT following conditioning with lethal and sublethal irradiation. In contrast, DNAM-1 was not critical for GVL effects against ligand (CD155) expressing and nonexpressing leukemia. The effects on GVHD following myeloablative conditioning were independent of CD8(+) T cells and dependent on CD4(+) T cells, and specifically donor FoxP3(+) regulatory T cells (Treg). The absence of DNAM-1 promoted the expansion and suppressive function of Treg after BMT. These findings provide support for therapeutic DNAM-1 inhibition to promote tolerance in relevant inflammatory-based diseases characterized by T-cell activation.
authors: The Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia. Motoko.Koyama@qimr.edu.au
authors: Motoko
authors: M
authors: Koyama
authors: Rachel D
authors: RD
authors: Kuns
authors: Stuart D
authors: SD
authors: Olver
authors: Katie E
authors: KE
authors: Lineburg
authors: Mary
authors: M
authors: Lor
authors: Bianca E
authors: BE
authors: Teal
authors: Neil C
authors: NC
authors: Raffelt
authors: Lucie
authors: L
authors: Leveque
authors: Christopher J
authors: CJ
authors: Chan
authors: Renee J
authors: RJ
authors: Robb
authors: Kate A
authors: KA
authors: Markey
authors: Kylie A
authors: KA
authors: Alexander
authors: Antiopi
authors: A
authors: Varelias
authors: Andrew D
authors: AD
authors: Clouston
authors: Mark J
authors: MJ
authors: Smyth
authors: Kelli P A
authors: KP
authors: MacDonald
authors: Geoffrey R
authors: GR
authors: Hill
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry / Q000502:physiology*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D007942:Leukemia, Experimental / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019172:Transplantation Conditioning; D014407:Tumor Cells, Cultured; D014916:Whole-Body Irradiation; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse