title: α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics.
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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Oncology, University of Washington, Seattle, WA;
authors.forename: A Mario
authors.initials: AM
authors.lastname: Marcondes
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Ekapun
authors.initials: E
authors.lastname: Karoopongse
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Marina
authors.initials: M
authors.lastname: Lesnikova
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Daciana
authors.initials: D
authors.lastname: Margineantu
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.affiliation: Department of Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; and Department of Medicine, University of Colorado Denver, Aurora, CO.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Oncology, University of Washington, Seattle, WA;
authors.forename: David
authors.initials: D
authors.lastname: Hockenbery
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany;
authors.forename: Sabina
authors.initials: S
authors.lastname: Janciauskiene
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Oncology, University of Washington, Seattle, WA;
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
mesh_terms: D000818:Animals; D039521:CD11c Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003710:Demography; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007773:Lactates / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D035781:Siblings; D013481:Superoxides / Q000378:metabolism; D014019:Tissue Donors; D015854:Up-Regulation / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000494:pharmacology*
chemical_list: D039521:CD11c Antigen; D007773:Lactates; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000515:alpha 1-Antitrypsin; D013481:Superoxides