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Blood. 2014 Oct 30;124(18):2881-91. doi: 10.1182/blood-2014-04-570440. Epub 2014 Sep 15.

α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics.

Author information

1
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Oncology, University of Washington, Seattle, WA;
2
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
3
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany;
4
Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; and Department of Medicine, University of Colorado Denver, Aurora, CO.

Abstract

Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8(+)CD11c(+)CD205(+) major histocompatibility complex class II(+) dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1(+), CD49B(+), CD122(+), CD335(+) NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis-high oxidative phosphorylation profile for NK1.1(+) cells, CD4(+)CD25(+)FoxP3(+) T cells, and CD11c(+) DCs but not for effector T cells, suggesting a cell type-specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects.

PMID:
25224412
PMCID:
PMC4215316
DOI:
10.1182/blood-2014-04-570440
[Indexed for MEDLINE]
Free PMC Article

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