title: Induction of alloantigen-specific T cell tolerance through the treatment of human T lymphocytes with wortmannin.
abstract: Signaling through the CD28 molecule on T cells by its natural ligand, B7, on APCs has recently been shown to require the presence of an active phosphatidylinositol 3-kinase pathway to mediate some of its costimulatory activities (1-7). Using the phosphatidylinositol 3-kinase inhibitor, wortmannin (WN) (8), on human and murine T cells, we have inhibited B7-1-mediated T cell activation and induced Ag-specific tolerance. The addition of WN and/or the B7-1 antagonist, CTLA4Ig, to primary human T cell cultures stimulated with B7-1-transfected allogeneic melanoma cell lines inhibited the generation of alloantigen-specific proliferative and cytolytic responses in vitro. Subsequent examination of these WN- and CTLA4Ig-treated primary T cell cultures revealed that these lymphocyte populations were tolerized to rechallenge with the priming alloantigens in secondary cultures in the absence of additional inhibitor(s). However, reactivity to a third party allogeneic stimulator remained intact. This WN-induced tolerance was reversed by the addition of high dose IL-2, but not IL-4 or IL-7, to the primary cultures, indicating that T cell anergy, not deletion, was responsible for this phenomenon. In vivo studies using a murine graft-vs-host disease (GVHD) model demonstrated that WN treatment of allogeneic donor lymphocytes in vitro failed to generate a significant GVHD in irradiated mouse recipients compared with control allogeneic donor lymphocytes. These findings suggest potentially novel therapeutic strategies for the prevention of GVHD.
authors.affiliation: Clinical Services Program, National Cancer Institute-Frederick Cancer Research and Development Program, MD 21702, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Taub
authors.forename: W J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: O
authors.initials: O
authors.lastname: Asai
authors.forename: R G
authors.initials: RG
authors.lastname: Fenton
authors.forename: G
authors.initials: G
authors.lastname: Peltz
authors.forename: M L
authors.initials: ML
authors.lastname: Key
authors.forename: S
authors.initials: S
authors.lastname: Turcovski-Corrales
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D000069594:Abatacept; D000730:Androstadienes / Q000494:pharmacology* / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D060908:CTLA-4 Antigen; D017635:Clonal Anergy / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology*; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D000939:Epitopes; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015851:Interleukin-7; D007519:Isoantigens; D015847:Interleukin-4; D000069594:Abatacept; D000077191:Wortmannin