A. Helicobacter hepaticus-induced colitis in IL-10-deficient mice: reversal of established disease by IL-12 neutralization. We have recently shown (Kullberg, et al., 1998) that specific pathogen-free IL- 10-deficient (IL-10 KO) mice develop colitis after infection with a defined enteropathogen, Helicobacter hepaticus. The disease is accompanied by a Th1-type response as measured by IFN-gamma and TNF- alpha production by mesenteric lymph node (MLN) cells stimulated with SHelAg, a soluble H. hepaticus Ag preparation. In contrast, C57BL/10 wild-type mice do not develop disease after inoculation with the same bacteria and their MLN cells secrete mainly IL-10 in response to SHelAg. To investigate the role of IL-12 in disease pathogenesis, IL-10 KO mice were treated with either anti-IL-12 or anti-IFN-gamma mAb from the start of the infection. Both groups of mAb-treated mice showed markedly diminished large bowel pathology. More interestingly, administration of anti-IL-12 to mice with an already established H. hepaticus-induced colitis also resulted in significantly reduced intestinal pathology. In this protocol, however, anti-IFN-gamma was only marginally effective. Administration of anti-IL-12 from the start of the infection led to diminished in vitro IFN-gamma secretion by SHelAg-stimulated MLN cells, an effect that was less pronounced in mice receiving anti-IL-12 during established disease. These results indicate that IL-12 is required for both the development and maintenance of the H. hepaticus-induced pathological response in IL-10 KO mice, and support the concept that neutralization of IL-12 activity and/or blockade of its receptor may be a useful approach for treatment of inflammatory bowel disease. B. Regulation of IL-10 production and fibrosis in Mycobacterium avium infection. We studied the induction of IL-10, an important downregulatory cytokine, during infection of mice with M. avium. Interestingly, synthesis of the cytokine by spleen cells did not reach peak levels until about 3-4 wks post-infection at which time it was maintained as the dominant cytokine synthesized. In contrast, IFN-gamma responses peaked at 2 wk post-infection and rapidly declined. While addition of anti-CD4 blocked the in vitro IFN-gamma response, the antibody failed to inhibit IL-10 production suggesting that macrophages (or possibly CD8+ T lymphocytes) rather than CD4 T cells are responsible for the latter. Splenocytes from infected IL-12- deficient mice also produced potent IL-10 responses demonstrating that in this infection, IL-10 is not induced as a direct consequence of IL- 12/IFN-gamma synthesis. Surprisingly, however, in the IL-12 KO animals the M. avium-triggered IL-10 response was inhibitable with anti-CD4 suggesting a switch in its cellular source. In related work, we studied the development of tissue fibrosis in M. avium-infected mice. High levels of collagen (as measured by hydroxyproline) were found in livers of 4-6 week infected mice. Interestingly, this pathologic parameter was markedly reduced in IL-12-deficient mice which show increased bacterial loads. The latter observation suggests that fibrosis is an unwanted consequence of the host IL-12- dependent protective immune response against mycobacteria. - Helicobacter, Mycobacterium avium, inflammatory bowel disease, IL-12, IL-10 fibrosis, immunoregulation
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