| First Author | Fevery S | Year | 2007 |
| Journal | Leukemia | Volume | 21 |
| Issue | 7 | Pages | 1451-9 |
| PubMed ID | 17508005 | Mgi Jnum | J:122783 |
| Mgi Id | MGI:3715431 | Doi | 10.1038/sj.leu.2404720 |
| Citation | Fevery S, et al. (2007) CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease. Leukemia 21(7):1451-9 |
| abstractText | 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. |
