title: Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions.
abstract: A murine model of minor histocompatibility antigen (miHCag)-mismatched bone marrow transplantation (BMT) was used to study the development of immunoregulatory cells in the posttransplantation period and their possible involvement in the dissociated graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity of posttransplantation donor lymphocyte infusions (DLIs). DLI, applied immediately after BMT, induced GVH disease (GVHD), but when DLI was delayed for 3 weeks, GVHD was avoided while a distinct GVL response was allowed to develop. A population of Mac1+Ly6-G+Ly6-C+ immature myeloid cells, found in small numbers in normal mice, strongly expanded in spleens of chimeras, reaching a maximum level at week 3 and returning to base level by week 12. Upon isolation, these cells exhibited interferon-gamma (IFN-gamma)-dependent, nitric oxide (NO)-mediated suppressor activity toward in vitro alloresponses, suggesting that, after in vivo DLI, they are activated by IFN-gamma to produce NO and suppress GVH reactivity. Because not only alloactivated T-cell proliferation but also leukemia cell growth was found susceptible to inhibition by exogenous NO, in vivo activation of these cells after DLI may explain the occurrence of a GVL effect despite suppression of GVHD. This suggested sequence of events was supported by the finding that the ex vivo antihost proliferative response of spleen cells, recovered shortly after in vivo DLI, was characterized by strong mRNA production of the monokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) and of inducible nitric oxide synthase (iNOS). Our data suggest that transiently expanding Mac1+Ly6-G+Ly6-C+ immature myeloid cells (probably as a result of extramedullary myelopoiesis) may play a role in controlling GVH while promoting GVL reactivity of DLI after allogeneic BMT.
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, Belgium.
authors.forename: An D
authors.initials: AD
authors.lastname: Billiau
authors.forename: Sabine
authors.initials: S
authors.lastname: Fevery
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.forename: Willy
authors.initials: W
authors.lastname: Landuyt
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis*; D002455:Cell Division; D005260:Female; D005786:Gene Expression Regulation; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology; D007108:Immune Tolerance; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D017710:Lymphocyte Transfusion; D016177:Macrophage-1 Antigen / Q000032:analysis*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D022423:Myeloid Cells / Q000737:chemistry / Q000276:immunology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011828:Radiation Chimera; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D013154:Spleen / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D019172:Transplantation Conditioning; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000950:Antigens, Ly; D006183:H-2 Antigens; D007375:Interleukin-1; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse