期刊
JOURNAL OF IMMUNOLOGY
卷 192, 期 12, 页码 6092-6101出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302771
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资金
- National Institutes of Health Training [T32 DK077662]
- National Institutes of Health Directors New Innovator Award [DP2 DK083099]
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-gamma and to exhibit an enhanced responsiveness to IFN-gamma by expressing higher levels of downstream effector molecules ido and nos2. Consequently, neutralization of IFN-gamma 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-gamma-dependent mechanisms. This form of preemptive donor apoptotic cell infusions has significant potential for the therapeutic manipulation of MDSCs for transplant tolerance induction.
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