Murine model of oral tolerance. Induction of Fas-mediated apoptosis by blockade of interleukin-12.

Abstract

We explored the immunological mechanisms underlying the development of oral tolerance with the use of ovalbumin (OVA) T-cell receptor (TCR)-transgenic mice. Feeding high doses of OVA induced tolerance in the peripheral lymphoid tissues, and the degree of peripheral tolerance was enhanced when antigen feeding was combined with systemic administration of antibodies to interleukin-12 (anti-IL-12). Using the TUNEL technique by which apoptotic cells can be specifically identified, we found evidence that peripheral clonal deletion occurs in OVA-TCR transgenic mice in vivo after oral antigen delivery and treatment with anti-IL-12, but only to a minor degree after antigen feeding alone. The mechanism that accounts for the dramatic loss of peripheral cells is Fas-mediated, since > 90% of antigen-specific Fas+ T cells were lost. In addition, antagonizing Fas but not TNF reversed the phenomenon when cells were stimulated in vitro. These findings suggest that IL-12 negatively regulates apoptosis, a major mechanism of peripheral tolerance. A combination of oral antigen feeding and administration of anti-IL-12 may thus be useful in the treatment of autoimmune diseases and may be a potent means to modulate peripheral tolerance.