Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.
We have described a murine model of IBD that was induced in C.B-17 scid mice by transfer of the CD45RBhi subpopulation of CD4+ T cells from normal BALB/c mice and could be prevented by cotransfer of the CD45RBlo CD4+ T cell subset. Here we have dissected the mechanism of pathogenesis of IBD in this model and used this information for rational immunotherapy of the disease. CD4+ cells from diseased mice displayed a highly polarized Th1 pattern of cytokine synthesis upon polyclonal stimulation in vitro. The administration of anti-IFN gamma MAb to mice soon after T cell transfer prevented development of colitis for up to 12 weeks. Continual neutralization of TNF with anti-TNF MAbs reduced the incidence of severe disease; however, neutralization of TNF during only the first 3-4 weeks had no effect. Severe colitis was completely abrogated in mice treated systemically with rIL-10, but not with rIL-4.
Powrie
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DNAX Research Institute of Molecular and Cellular Biology Incorporated, Palo Alto, California 94040, USA.
Leach
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MW
Mauze
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Menon
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Caddle
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Coffman
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RL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D003092:Colitis / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D018448:Models, Immunological; D012333:RNA, Messenger / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D000911:Antibodies, Monoclonal; D007378:Interleukins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens