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Alloantigen expression on malignant cells and healthy host tissue influences graft-versus-tumor reactions after allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 53, pages 807–819 (2018)Cite this article

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Abstract

Durable remissions of hematological malignancies regularly observed following allogeneic hematopoietic stem cell transplantation (aHSCT) are due to the conditioning regimen, as well as an immunological phenomenon called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. The development of GVL is closely linked to graft-versus-host disease (GVHD), the main side effect associated with aHSCT. Both, GVHD and GVL are mediated by donor T cells that are initially activated by antigen-presenting cells that present recipient-derived alloantigens in the context of either matched or mismatched MHC class I molecules. Using murine models of aHSCT we show that ubiquitously expressed minor histocompatibility alloantigens (mHAg) are no relevant target for GVT effects. Interestingly, certain ubiquitously expressed MHC alloantigens augmented GVT effects early after transplantation, while others did not. The magnitude of GVT effects correlated with tumor infiltration by CD8+ cytotoxic T cells and tumor cell apoptosis. Furthermore, the immune response underlying GVHD and GVT was oligoclonal, highlighting that immunodominance is an important factor during alloimmune responses. These results emphasize that alloantigen expression on non-hematopoietic tissues can influence GVT effects in a previously unrecognized fashion. These findings bear significance for harnessing optimal GVL effects in patients receiving aHSCT.

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Acknowledgements

This work was supported by grants from the German José Carreras Leukemia-Foundation (DJCLS R 05/35, R 08/31 f)

Author contributions

S.R., K.F., C.O., J.U., C.W., and C.H., helped to design the experiments and performed experiments; M.S. developed the overall concept; S.R., J.C.A., K.F., W.E.B., and M.S. analyzed and discussed the data and wrote the manuscript.

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  1. Stella Robert, Jörn C. Albring, and Karin Frebel are co-first authors.

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  1. Department of Medicine A, University Hospital of Muenster, Muenster, Germany

    Stella Robert, Jörn C. Albring, Karin Frebel, Corinna Opitz, Jennifer Urh, Claudia Wolf, Christine Heinrich, Wolfgang E. Berdel & Matthias Stelljes

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  1. Stella Robert
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Robert, S., Albring, J.C., Frebel, K. et al. Alloantigen expression on malignant cells and healthy host tissue influences graft-versus-tumor reactions after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 53, 807–819 (2018). https://doi.org/10.1038/s41409-017-0071-7

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