title: CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease.
abstract: We studied the effect of CTLA-4 blockade on graft-versus-leukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively host-derived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Fevery
authors.forename: A D
authors.initials: AD
authors.lastname: Billiau
authors.forename: B
authors.initials: B
authors.lastname: Sprangers
authors.forename: O
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: C
authors.initials: C
authors.lastname: Lenaerts
authors.forename: J
authors.initials: J
authors.lastname: Goebels
authors.forename: W
authors.initials: W
authors.lastname: Landuyt
authors.forename: A
authors.initials: A
authors.lastname: Kasran
authors.forename: L
authors.initials: L
authors.lastname: Boon
authors.forename: X
authors.initials: X
authors.lastname: Sagaert
authors.forename: C
authors.initials: C
authors.lastname: De Wolf-Peeters
authors.forename: M
authors.initials: M
authors.lastname: Waer
authors.forename: P
authors.initials: P
authors.lastname: Vandenberghe
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects* / Q000276:immunology; D000943:Antigens, Differentiation / Q000187:drug effects* / Q000276:immunology; D015551:Autoimmunity; D016026:Bone Marrow Transplantation; D060908:CTLA-4 Antigen; D006086:Graft vs Host Disease; D020544:Graft vs Leukemia Effect; D006648:Histocompatibility; D007938:Leukemia / Q000628:therapy; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse