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Animal Models

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

Leukemia volume 26, pages 312–322 (2012)Cite this article

Abstract

Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4+ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4+ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4+ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4+ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4+ T cells. In conclusion, our results show that CD4+ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4+ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4+ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.

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Acknowledgements

We thank ED van der Meijden (Leiden University Medical Center, Department of Hematology) for generation of HLA-DQ constructs. This study was supported by grant 2008-4263 from the Dutch Cancer Society.

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Authors and Affiliations

  1. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    S Stevanović, M Griffioen, M L J van Schie, A N Stumpf, C E Rutten, R Willemze & J H F Falkenburg

  2. Amsterdam Molecular Therapeutics, Amsterdam, The Netherlands

    B A Nijmeijer

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  1. S Stevanović
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  2. M Griffioen
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  3. B A Nijmeijer
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  4. M L J van Schie
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  8. J H F Falkenburg
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Correspondence to S Stevanović.

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Stevanović, S., Griffioen, M., Nijmeijer, B. et al. Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia. Leukemia 26, 312–322 (2012). https://doi.org/10.1038/leu.2011.222

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