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Stem Cells

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

Leukemia volume 21, pages 1451–1459 (2007)Cite this article

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.

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Acknowledgements

This work was supported by grants from the Flanders National Fund for Scientific Research and the Belgian Federation against Cancer. Sabine Fevery holds a grant from the Flanders National Fund for Scientific Research. Ben Sprangers is a doctoral fellow, An D Billiau a postdoctoral fellow and P Vandenberghe a senior clinical investigator of the Flanders National Fund for Scientific Research. We thankfully acknowledge expert assistance of Karen Moermans (Laboratory of Experimental Medicine and Endocrinology, University of Leuven), Lieve Ophalvens,5 Katleen Van Meerbeek,5 Erna Van Dissel5 and Dr Gert De Hertogh.5 We thank the staff of the animal facility for providing excellent animal care.

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  1. S Fevery and A D Billiau: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium

    S Fevery, A D Billiau, B Sprangers, O Rutgeerts, C Lenaerts, J Goebels & M Waer

  2. Laboratory of Oncology and Experimental Radiobiology, University of Leuven, Leuven, Belgium

    W Landuyt

  3. Laboratory of Experimental Immunology, University of Leuven, Leuven, Belgium

    A Kasran

  4. Pre-Clinical R&D, Bioceros BV, Utrecht, The Netherlands

    L Boon

  5. Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium

    X Sagaert & C De Wolf-Peeters

  6. Center of Human Genetics, University of Leuven, Leuven, Belgium

    P Vandenberghe

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Fevery, S., Billiau, A., Sprangers, B. et al. CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease. Leukemia 21, 1451–1459 (2007). https://doi.org/10.1038/sj.leu.2404720

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