B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality Journal Article

Authors: Veenstra, R. G.; Flynn, R.; Kreymborg, K.; McDonald-Hyman, C.; Saha, A.; Taylor, P. A.; Osborn, M. J.; Panoskaltsis-Mortari, A.; Schmitt-Graeff, A.; Lieberknecht, E.; Murphy, W. J.; Serody, J. S.; Munn, D. H.; Freeman, G. J.; Allison, J. P.; Mak, T. W.; Van Den Brink, M.; Zeiser, R.; Blazar, B. R.
Article Title: B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality
Abstract: Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H32/2 vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H32/2 vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H32/2 Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications. © 2015 by The American Society of Hematology.
Keywords: immunohistochemistry; allograft; flow cytometry; polymerase chain reaction; t lymphocyte; t-lymphocytes; mouse; animal; animals; mice; immunology; graft versus host reaction; bone marrow transplantation; graft vs host disease; b7 antigen; adverse effects; allografts; b7 antigens; humans; human; absence of b7-h3 expression in allogeneic recipients or on allogeneic donor t cells leads to accelerated gvhd lethality. increased gvhd lethality is a result of increased t-cell proliferation; colon inflammatory cytokines, and intestinal permeability; cd276 protein, mouse
Journal Title: Blood
Volume: 125
Issue: 21
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2015-05-21
Start Page: 3335
End Page: 3346
Language: English
DOI: 10.1182/blood-2014-09-603357
PUBMED: 25814530
PROVIDER: scopus
PMCID: PMC4440885
Notes: Article -- Export Date: 1 September 2016 -- Source: Scopus
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  1. James P Allison
    129 Allison