CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease.
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.
Fevery
S
S
Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium.
Billiau
A D
AD
Sprangers
B
B
Rutgeerts
O
O
Lenaerts
C
C
Goebels
J
J
Landuyt
W
W
Kasran
A
A
Boon
L
L
Sagaert
X
X
De Wolf-Peeters
C
C
Waer
M
M
Vandenberghe
P
P
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
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse