Enhanced oral tolerance in transgenic mice with hepatocyte secretion of IL-10.
Several cytokines derived from Th3 and Tr1 cells, including IL-10, are believed to regulate oral tolerance, but direct evidence is lacking. We have explored the potential role of IL-10 by generating transgenic (TG) mice with sustained hepatocyte-specific expression of rat IL-10. TG mice expressed rat IL-10 downstream of a transthyretin promoter, which led to serum levels that were increased 10- to 100-fold compared with normal animals. Animals were orally administered 1 mg of whole OVA for 5 consecutive days, with control animals receiving PBS. There were six animal groups: Either OVA or PBS were fed orally to rat IL-10 TG mice, non-TG wild-type mice without IL-10 administration, and non-TG wild-type mice administered rat IL-10 systemically. On day 8, all mice were immunized with two injections of OVA, and then analyzed on day 18. T cell proliferation responses were reduced by 65.8 +/- 14.3% after feeding of OVA in rIL-10 TG animals, compared with 39.4 +/- 15.6% in the non-TG mice (p = 0.02). Anti-OVA titers were expressed as fold increase over naive non-TG mice. After feeding, titers decreased by approximately 33% (from 3- to 2-fold) in TG animals and, to a lesser extent, in non-TG animals. IFN-gamma secretion by cultured popliteal lymphocytes decreased in TG animals by 83% after feeding and by 69% in non-TG animals. IL-4 secretion increased 4-fold in TG-fed mice, but did not significantly change in non-TG OVA-fed animals. In contrast to hepatic TG expression of rIL-10, systemic administration of rIL-10 had only a modest effect on tolerance. IL-10, when transgenically expressed in the liver enhances mucosal tolerance to an oral Ag.
Safadi
Rifaat
R
Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA.
Alvarez
Carlos E
CE
Ohta
Masayuki
M
Brimnes
Jens
J
Kraus
Thomas
T
Mehal
Wajahat
W
Bromberg
Jonathan
J
Mayer
Lloyd
L
Friedman
Scott L
SL
D000284:Administration, Oral; D000818:Animals; D000906:Antibodies / Q000097:blood; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance; D007114:Immunization; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009061:Mouth Mucosa / Q000276:immunology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D016753:Interleukin-10; D015847:Interleukin-4; D010047:Ovalbumin