1. IFN-γ-induced iNOS expression in mouse regulatory macrophages prolongs allograft survival in fully immunocompetent recipients.
- Author
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Riquelme P, Tomiuk S, Kammler A, Fändrich F, Schlitt HJ, Geissler EK, and Hutchinson JA
- Subjects
- Animals, Cell Proliferation drug effects, Cytokines metabolism, Dendritic Cells cytology, Dendritic Cells metabolism, Flow Cytometry, Gene Expression Regulation, Humans, Macrophage Colony-Stimulating Factor pharmacology, Macrophages metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Microarray Analysis, Monocytes cytology, Monocytes metabolism, Nitric Oxide Synthase Type II metabolism, Phenotype, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Transplantation, Homologous, Graft Survival, Heart Transplantation methods, Immunosuppression Therapy methods, Interferon-gamma pharmacology, Macrophages drug effects, Nitric Oxide Synthase Type II genetics
- Abstract
Mouse monocytes exposed to macrophage colony-stimulating factor (M-CSF) and interferon-γ (IFN-γ) were driven to a novel suppressor phenotype. These regulatory macrophages (M regs) expressed markers distinguishing them from M0-, M1-, and M2-polarized macrophages and monocyte-derived dendritic cells (DCs). M regs completely suppressed polyclonal T cell proliferation through an inducible nitric oxide synthase (iNOS)-dependent mechanism. Additionally, M regs eliminated cocultured T cells in an allospecific fashion. In a heterotopic heart transplant model, a single intravenous administration of 5 × 10(6) donor-strain M regs before transplantation significantly prolonged allograft survival in fully immunocompetent recipients using both the stringent C3H-to-BALB/c (32.6 ± 4.5 versus 8.7 ± 0.2 days) and B6-to-BALB/c (31.1 ± 12 versus 9.7 ± 0.4 days) strain combinations. Nos2-deficient M regs did not prolong allograft survival, proving that M reg function in vivo is iNOS-dependent and mediated by living cells. M regs were detectable for at least 2 weeks postinfusion in allogeneic recipients. In their origin, development, phenotypic relationship with other in vitro-derived macrophages and functions, there are solid grounds to assert a near-equivalence of mouse and human M regs. It is concluded that mouse M regs represent a novel, phenotypically distinct subset of suppressor macrophages. Clinical applications of M reg therapy as an adjunct immunosuppressive therapy are currently being investigated within The ONE Study.
- Published
- 2013
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