'Timing is everything': A differential role for cytokines in the development of experimental autoimmune thyroiditis

Many factors are likely to influence whether an individual will develop overt autoimmune disease, including genetics of the host and the method used to terminate self-tolerance. In this study we compared the immune response of two inbred strains of mice in the development of experimental autoimmune thyroiditis (EAT). CBA/J mice typically respond to immunization with mouse thyroglobulin (mTg) by developing overt thyroid disease and anti-mTg IgG titers. BALB/c mice usually respond to immunization by developing an autoantibody titer but little or no disease. Our initial hypothesis was that the difference between the susceptible CBA/J and the resistant BALB/c mice resided in the balance of cytokines incited by the immunization.; We explored the role of IL-12 in the pathogenesis of EAT using a novel disease paradigm that distinguishes three stages of disease, from the priming of disease, through its initiation in the thyroid, and leading to the progression of destruction. We found that neutralization of IL-12 during disease priming markedly suppressed the development of disease, globally suppressed autoantibody production, and resulted in long-term alterations in mTg.-specific in vitro splenocyte cytokine production. Neutralization of IL-12-during the initiation of disease significantly suppressed disease but only anti-mTg IgG2a titers were reduced. However, blocking IL-12 after disease was established did not alter the measured disease parameters in the time frame we studied. Thus there may be a shift from IL-12-dependent to IL-12-independent mechanisms as disease progresses.; We found treating resistant BALB/c mice with exogenous rmIL-12 at any time during the course of disease did not alter disease levels. Susceptible CBA/J mice showed a significant acceleration of disease and a trend toward more severe EAT when treated early in the course of disease. When treated after disease was established, CBA/J mice had a trend toward less severe disease. Differences in strain susceptibility to IL-12 may underlie important mechanisms that maintain self-tolerance in some individuals but not in others in the face of an autoimmune challenge.