1. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality.
- Author
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Veenstra, Rachelle G., Flynn, Ryan, Kreymborg, Katharina, McDonald-Hyman, Cameron, Saha, Asim, Taylor, Patricia A., Osborn, Mark J., Panoskaltsis-Mortari, Angela, Schmitt-Graeff, Annette, Lieberknect, Elisabeth, Murphy, William J., Serody, Jonathan S., Munn, David H., Freeman, Gordon J., Allison, James P., Mak, Tak W., van den Brink, Marcel, Zeiser, Robert, and Blazar, Bruce R.
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GRAFT versus host disease , *CELL proliferation , *IMMUNOREGULATION , *CYTOKINE genetics , *T cells , *BONE marrow transplant complications , *PREVENTION , *THERAPEUTICS - 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-H3-/- 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-H3-/- 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-H3-/- 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 DLl-mediated GVL without GVHD complications. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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