Regulation of experimental mucosal inflammation.
Studies conducted over the past 10 years have provided ample evidence that many types of inflammations arising from basic abnormalities of immune regulation are ultimately 'funneled' through a Th1 or Th2 T cell-mediated immune reaction. Thus, by understanding these types of reactions and, in particular, by identifying their natural checkpoints, one can control the inflammation regardless of its more basic causes. A case in point is the inflammatory disease of the intestine known as Crohn disease, a disease now thought to be due to one or more abnormalities leading to an excessive immune response to elements of the bacterial microflora of the gut. Both in murine models and by study of Crohn disease itself, we have shown that Crohn inflammation is due to a Th1 T-cell abnormality involving overproduction of interleukin (IL)-12, interferon (IFN-gamma, and tumor necrosis factor (TNF)-alpha. In addition, we and others have shown that treatment of mice with anti-IL-12 or other agents that downregulate the level of IL- 12 secretion can have a dramatic effect on the inflammation. This is because anti-IL-12 administration leads to apoptosis of activated Th1 T cells. A second checkpoint of Th1 T-cell-mediated inflammation involves its downregulation by the suppressor cytokine, transforming growth factor (TGF)-beta. We have been delivering TGF-beta to mice with experimental intestinal inflammation, using several novel approaches. In particular, we have successfully treated such mice with intranasally administered DNA encoding active TGF-beta. Another approach currently under investigation is delivery of TGF-beta by gene therapy. These and other developments in the understanding of inflammation paint a bright future for cytokine-based therapeutic agents. It is now apparent that these therapies are not only effective and safe but also potentially long-lasting.
Strober
W
W
Mucosal Immunity Section, Laboratory of Clinical Investigation, NIAID, National Institute of Health, Bethesda, Maryland 20892-1890, USA. wstrober@niaid.nih.gov
Fuss
I
I
Kitani
A
A
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000628:therapy*; D015536:Down-Regulation; D018014:Gene Transfer Techniques; D007167:Immunotherapy / Q000379:methods*; D016753:Interleukin-10 / Q000627:therapeutic use; D018664:Interleukin-12 / Q000037:antagonists & inhibitors; D007413:Intestinal Mucosa / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D014302:Trinitrobenzenesulfonic Acid