Th1 cytokines and NK cells participate in the development of murine syngeneic graft-versus-host disease.
Syngeneic graft-vs-host disease (SGVHD) is induced by reconstituting lethally irradiated mice with syngeneic bone marrow cells followed by a short course of therapy with the immunosuppressive agent cyclosporine A. Following cessation of cyclosporine A therapy, animals develop clinical symptoms of SGVHD: weight loss, runting, and diarrhea. While it has been suggested that T cells are responsible for the induction and effector phases of SGVHD, the role of nonspecific effector cells and cytokine mediators has yet to be examined in the disease process. Mice with SGVHD had increased levels of message for IL-12p40, IFN-gamma, and TNF-alpha in the target organs of SGVHD as compared with transplant controls and asymptomatic cyclosporine A-treated mice. Concomitant with the increase in Th1 cytokines was an enhanced cellular infiltrate in the target organs of SGVHD mice as determined by histological analysis. To directly examine the role of IL-12 in the development of SGVHD, in vivo neutralization of IL-12 was performed. Treatment of mice with Abs to IL-12 inhibited SGVHD-mediated tissue pathology and mortality. Because IL-12 has been shown to activate both T cells and NK cells to secrete IFN-gamma and to become more cytolytic, studies were initiated to ascertain which lymphocyte populations play a role in the development of murine SGVHD. Depletion of NK cells inhibited clinical symptoms of SGVHD. In contrast, T cell depletion did not alter the disease process. Therefore, these findings collectively demonstrate a role for IL-12 and NK cells in the effector phase of murine SGVHD.
Department of Microbiology, Department of Pathology, Division of Hematology/Oncology, Markey Cancer Center, University of Kentucky, Lexington 40536, USA.
D L
DL
Flanagan
C D
CD
Jennings
J S
JS
Bryson
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface; D003106:Colon / Q000276:immunology / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008212:Lymphocyte Depletion; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014185:Transplantation, Isogeneic
D000911:Antibodies, Monoclonal; D000941:Antigens; D000954:Antigens, Surface; D016207:Cytokines; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D012333:RNA, Messenger; D018664:Interleukin-12; D016572:Cyclosporine