Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12.
There is now increasing evidence that hyperresponsiveness towards intestinal flora is a crucial event in the pathogenesis of inflammatory bowel disease (IBD). In support of this hypothesis, we recently described in humans that tolerance exists towards indigenous intestinal flora but is broken in active IBD lesions. In the present study, we have attempted to transfer this model into mice from different genetic backgrounds (BALB/c, SJL/J, C3H/HeJ). We found that mononuclear cells from spleen, small bowel and large bowel of mice do not proliferate, i.e. are tolerant when exposed to bacterial sonicates derived from autologous intestine (BsA) but do proliferate, i.e. are immune when exposed to bacterial sonicates derived from the heterologous intestine of syngenic littermates (BsH). Furthermore, we demonstrate that both local and systemic tolerance to BsA is broken in a murine model of chronic intestinal inflammation induced by the hapten reagent 2, 4, 6-trinitrobenzene sulfonic acid (TNBS), which mimics several important characteristics of Crohn's disease. Tolerance to BsA was restored and TNBS-induced colitis was abrogated in mice systemically treated with interleukin (IL)-10 or antibodies to IL-12. Treatment specifically restored tolerance to BsA, but did not suppress proliferation to BsH. In summary, we here report a new model for the study of immunity and tolerance towards bacterial products. Our data suggest that tolerance to BsA is an important protective mechanism and that restoration of tolerance intestinal flora by IL-10 and antibodies to IL-12 may be of potential therapeutic utility in patients with inflammatory bowel disease.
Duchmann
R
R
I. Department of Medicine, University of Mainz, Germany.
Schmitt
E
E
Knolle
P
P
Meyer zum Büschenfelde
K H
KH
Neurath
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001419:Bacteria / Q000276:immunology* / Q000302:isolation & purification; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology / Q000628:therapy; D003106:Colon / Q000166:cytology / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007155:Immunologic Factors / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000276:immunology; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology; D007422:Intestines / Q000382:microbiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010581:Peyer's Patches / Q000166:cytology / Q000276:immunology; D051381:Rats; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D014302:Trinitrobenzenesulfonic Acid