IMMUNOSUPPRESSION OF THYROIDITIS

Immunization of mice with 50 mu g human thyroglobulin (TG) in complete Freund's adjuvant leads to histological thyroiditis; production of Ig G, IgA, and IgM anti-TG antibodies; and in vitro proliferative respons es after incubation of lymphocytes with TG. Oral administration of 500 mu g TG at four intervals before Tg immunization and once afterward c auses up to 80% suppression of these responses. The effect is antigen specific and dose dependent. Feeding TG after immunization produces a 40% reduction in responses. We wished to define the mechanism of this antigen-specific oral tolerization. Popliteal lymph nodes (PLN) of ora lly tolerized animals (T) are reduced in size compared to those in imm unized (I) animals not fed TG. PLN and mesenteric lymph nodes (MLN) of I animals produce interleukin-2 (IL-2) and interferon-gamma (IFN gamm a) after in vitro incubation with TG, typical of an inflammatory immun e response. PLN and MLN of tolerized animals do not proliferate in res ponse to antigen, do not produce IL-2 or IFN gamma, but do produce the cytokines IL-4 and transforming growth factor-beta (TGF beta). Mixing in vitro of spleen cells from T and I animals causes a reduction in t he immune response when incubated with TG, but no reduction in respons e to purified protein derivative (PPD) (the antigen in complete Freund 's adjuvant). When T splenocytes are incubated with TG and PPD togethe r, the response to TG and PPD is suppressed. Partially purified CD8(+) cells from tolerized animals produce IL-4 and TGF beta after exposure to human TG and induce suppression, whereas partially purified CD4(+) cells produce IL-2 and IFN gamma and do not cause suppression. MLN ce lls do not proliferate in response to antigen, but do produce inhibito ry cytokines. T animals appear to shift the immune response from a Th- 1 helper cell subset response to a Th-2 helper cell immunosuppressive response. In this model, oral tolerization produces a dramatic reducti on in the immune response. Exposure of MLN to oral TG appears to cause the production of regulatory cells that migrate to spleen and PLN. In vitro studies demonstrate that on exposure to antigen, these regulato ry cells produce IL-4 and TGF beta, which suppress all aspects of spec ific immune responsiveness and nonspecifically suppress other ongoing immune responses (bystander effect). Oral tolerization may include som e element of T cell deletion or anergy. This model defines an experime ntal system with possible relevance to immunosuppression of human auto immune thyroid disease.