title: IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity.
abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the GVL activity of these activated donor T cells and limit their graft versus host activity, we engineered the cellular constituents of an allogeneic hematopoietic stem cell graft with highly purified hematopoietic stem cells, T cells, and pre-pDCs and studied their GVL and GVHD activities in a murine model of allogeneic HSCT. Transplanted donor pre-pDCs expanded in vivo for 2 weeks after transplant, and they markedly augmented the activation and GVL activity of donor T cells while attenuating their GVHD activity, leading to an improved therapeutic index. Bidirectional signaling between donor T cells and donor pDCs with IFN-γ synthesis by donor T cells inducing indoleamine 2,3-dioxygenase synthesis by donor pDCs limited GVHD by altering the balance between donor T-reg and inflammatory T cells. Manipulating the content of donor DC precursors in allogeneic HSCT is a novel method to optimize the balance between GVL and GVHD.
authors: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University Medical School, 1365B Clifton Road NE, Atlanta, GA 30322, USA.
authors: Ying
authors: Y
authors: Lu
authors: Cynthia R
authors: CR
authors: Giver
authors: Akshay
authors: A
authors: Sharma
authors: Jian Ming
authors: JM
authors: Li
authors: Katarzyna A
authors: KA
authors: Darlak
authors: Lauren M
authors: LM
authors: Owens
authors: John D
authors: JD
authors: Roback
authors: Jacques
authors: J
authors: Galipeau
authors: Edmund K
authors: EK
authors: Waller
mesh_terms: D000818:Animals; D002450:Cell Communication; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000378:metabolism*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D000096743:Interferon gamma Receptor
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor