Oral administration of protein antigens induces immunologic tolerance to that protein, in contrast to systemic immunization that leads to sensitization. The investigators have recently demonstrated that oral tolerance is mediated, in part, by functional inactivation of the antigen-specific T lymphocytes. However, the mechanisms by which these antigen-specific T lymphocytes are inactivated upon exposure to orally administered antigen are not understood. The general hypothesis underlying the proposed studies is that oral administration of an antigen induces anergy by activating antigen-specific T lymphocytes to become a unique population of lymphocytes that are functionally nonresponsive. The objectives of this study are to determine the fate of antigen-specific T lymphocytes after oral administration of a specific antigen, and to identify which initial molecular and cellular interactions are required to induce oral tolerance. The long term goals of this work are to understand the mechanisms of tolerance induction and the relationship between the mucosal and systemic immune systems. Using the model system of the adoptive transfer of T-cell receptor transgenic T lymphocytes into naive BALB/c mice, the investigators will track the fate of the antigen-specific T-cells. They will distinguish between anergy and deletion as the mechanism of tolerance induction by using a monoclonal antibody that will identify the transgenic T-cells, in concert with antigen-specific functional assays. They will test the general hypothesis with the following specific aims: 1. Define the initial events that occur during tolerance induction. They will test the hypothesis that activation events occur prior to tolerance induction. 2. Define the temporal relationship between orally induced tolerance and systemic sensitization. Although they have shown that oral tolerance is effective in prevention of sensitization, they will ask whether previously immunized animals can be subsequently tolerized by oral administration of an antigen. 3. Define the tolerant state. The hypothesis that anergic T-cells are a parallel population to memory T-cells with a functional block will be tested by examining the surface expression of the activation and memory cell markers on Tg+ T-cells from DO11.10 into BALB/c chimeras. Activation-induced NFAT translocation and [Ca++]i mobilization in Tg+ T-cells will be measure in T-cells from tolerized animals to determine the functional block that dictates anergy. Several human autoimmune diseases are being treated by attempting to induce antigen-specific immune suppression via oral antigen feeding. While experimental models have shown clearly that oral administration of an antigen can prevent the induction of disease, it remains to be shown whether a specific oral antigen can tolerized previously sensitized animals, or autoimmune patients. Defining the mechanisms of the induction of anergy by oral tolerance will allow more effective applications of this potentially important immune manipulation for treatment of autoimmune disorders and prevention of transplantation rejection.
| Sun, Jiaren; Alison Stalls, M; Thompson, Katherine L et al. (2003) Cell cycle block in anergic T cells during tolerance induction. Cell Immunol 225:33-41 |
| Sun, Jiaren; Van Houten, Nancy (2002) CD40 stimulation in vivo does not inhibit CD4+ T cell tolerance to soluble antigens. Immunol Lett 84:125-32 |
| Sun, J; Dirden-Kramer, B; Ito, K et al. (1999) Antigen-specific T cell activation and proliferation during oral tolerance induction. J Immunol 162:5868-75 |
