title: Preemptive donor apoptotic cell infusions induce IFN-γ-producing myeloid-derived suppressor cells for cardiac allograft protection.
abstract: We have previously shown that preemptive infusion of apoptotic donor splenocytes treated with the chemical cross-linker ethylcarbodiimide (ECDI-SPs) induces long-term allograft survival in full MHC-mismatched models of allogeneic islet and cardiac transplantation. The role of myeloid-derived suppressor cells (MDSCs) in the graft protection provided by ECDI-SPs is unclear. In this study, we demonstrate that infusions of ECDI-SPs increase two populations of CD11b(+) cells in the spleen that phenotypically resemble monocytic-like (CD11b(+)Ly6C(high)) and granulocytic-like (CD11b(+)Gr1(high)) MDSCs. Both populations suppress T cell proliferation in vitro and traffic to the cardiac allografts in vivo to mediate their protection via inhibition of local CD8 T cell accumulation and potentially also via induction and homing of regulatory T cells. Importantly, repeated treatments with ECDI-SPs induce the CD11b(+)Gr1(high) cells to produce a high level of IFN-γ and to exhibit an enhanced responsiveness to IFN-γ by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-γ completely abolishes the suppressive capacity of this population. We conclude that donor ECDI-SPs induce the expansion of two populations of MDSCs important for allograft protection mediated in part by intrinsic IFN-γ-dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction.
authors.affiliation: Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Jane
authors.initials: J
authors.lastname: Bryant
authors.affiliation: Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Lerret
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and.
authors.forename: Jiao-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: Hee-Kap
authors.initials: HK
authors.lastname: Kang
authors.affiliation: Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
authors.forename: James
authors.initials: J
authors.lastname: Tasch
authors.affiliation: Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 xunrongluo@northwestern.edu.
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
mesh_terms: D064591:Allografts; D000818:Animals; D017209:Apoptosis; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation; D007371:Interferon-gamma / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000637:transplantation*
chemical_list: D007371:Interferon-gamma