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 re gulation art, ultimately 'funneled' through it Th1 or Th2 T cell-mediated i mmune reaction. Thus, by understanding these types of reactions and, in par ticular, by identifying their natural checkpoints, one can control the infl ammation regardless of its more basic causes. A case in point is the inflam matory disease of thc intestine known as Crohn disease, a disease now thoug ht to be due to one or more abnormalities leading to an excessive immune re sponse to elements of the bacterial microflora of the gut. Both ill murine models and by study of Crohn disease itself, we have shown that Crohn infla mmation is due to a Th1 T-cell abnormality involving overproduction of inte rleukin (IL)-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-al pha. 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 h ave a dramatic effect on the inflammation. This is because anti-IL-12 admin istration leads to apoptosis of activated Th1 T cells. A second checkpoint of Th1 T-cell-mediated inflammation involves its downregulation by the supp ressor cytokine, transforming growth factor (TGF)-beta. Wr have been delive ring TGF-beta to mice with experimental intestinal inflammation, using seve ral novel approaches. In particular, we have successfully treated such mice with intranasally administered DNA encoding active TGF-beta. Another appro ach currently under investigation is delivery of TGF-beta by gene therapy. These and other developments in the understanding of inflammation paint it bright future For cytokine-based therapeutic agents. It is now apparent tha t these therapies are not only effective and safe but also potentially long lasting.