title: Cutting edge: targeted ligation of CTLA-4 in vivo by membrane-bound anti-CTLA-4 antibody prevents rejection of allogeneic cells.
abstract: Natural engagement of CTLA-4 on host B7 limits T cell activation. We hypothesized that therapeutic cross-linking of CTLA-4 in vivo may further inhibit T cell function and prevent allograft rejection. However, none of the currently available CTLA-4-binding reagents have ligating properties when injected in vivo. The observation that surface-immobilized anti-CTLA-4 mAb inhibits T cell activation in vitro prompted us to develop a membrane-bound single-chain anti-CTLA-4 Ab (7M). To model whether tissue expression of 7M could suppress allograft rejection, we examined the ability of H-2L(d)-specific TCR-transgenic T cells to reject 7M-expressing allogeneic tumor cells injected s.c. Expression of 7M significantly inhibited allogeneic rejection in mice that received CTLA-4(+/+) but not CTLA-4(-/-) T cells. Furthermore, CTLA-4(+/+) T cells that had encountered 7M-expressing tumors in vivo acquired defects in cytokine production and cytotoxicity. Thus, deliberate ligation of CTLA-4 in vivo potently inhibits allogeneic T cell responses.
authors.affiliation: Department of Medicine and Committee in Immunology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kwang Woo
authors.initials: KW
authors.lastname: Hwang
authors.forename: William B
authors.initials: WB
authors.lastname: Sweatt
authors.forename: Ian E
authors.initials: IE
authors.lastname: Brown
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
mesh_terms: D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018390:Gene Targeting / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D007106:Immune Sera / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics; D018796:Immunoconjugates; D007519:Isoantigens / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D007106:Immune Sera; D018796:Immunoconjugates; D007519:Isoantigens; D000069594:Abatacept