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Graft-versus-host Disease

Apoptotic signaling through Fas and TNF receptors ameliorates GVHD in mobilized peripheral blood grafts

Bone Marrow Transplantation volume 49, pages 640–648 (2014)Cite this article

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Abstract

Mobilized peripheral blood (mPB) is a prevalent source of hematopoietic progenitors for transplantation; however, allogeneic and haploidentical transplants are often accompanied by severe GVHD. Following the observation that murine GVHD is ameliorated by pretransplant donor cell exposure to Fas-ligand (FasL) without host-specific sensitization, we assessed the susceptibility of mPB cells to spontaneous and receptor-induced apoptosis as a possible approach to GVHD prophylaxis. Short incubation for 4 h resulted in spontaneous apoptosis of 50% of the T and B lymphocytes and 60% myeloid cells. Although expression of Fas and TNF-R1 was proportionate to fractional apoptosis, cell death was dominated by spontaneous apoptosis. Functional assays revealed that the death receptors modulated mPB graft composition as compared with incubation in medium, without detectable quantitative variations. Removal of dead cells increased the frequency of mPB myeloid progenitors (P<0.001 vs medium), and recipients of mPB exposed to death ligands displayed reduced GVHD (P<0.01 vs medium) and improved survival following lipopolysacharide stimulation. mPB grafts exposed to the apoptotic challenge retained SCID reconstituting potential and graft versus tumor activity. These data emphasize that short-term exposure of mPB grafts to an apoptotic challenge is effective in reduction of GVHD effector activity.

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Acknowledgements

This work was funded by grants from the Frankel Trust for Experimental Bone Marrow Transplantation. We thank Mrs Ela Zuzovsky and Mrs Ana Zemliansky for their outstanding technical support.

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  1. Frankel Laboratory, Center for Stem Cell Research, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    K Mizrahi & N Askenasy

  2. Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    I Yaniv & S Ash

  3. Bone marrow Transplant Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel

    J Stein

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  1. K Mizrahi
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Correspondence to N Askenasy.

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Mizrahi, K., Yaniv, I., Ash, S. et al. Apoptotic signaling through Fas and TNF receptors ameliorates GVHD in mobilized peripheral blood grafts. Bone Marrow Transplant 49, 640–648 (2014). https://doi.org/10.1038/bmt.2014.12

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