Thyroid-infiltrating lymphocytes spontaneously synthesize IgG class thyroid autoantibodies while blood lymphocytes require activation to produce the same autoantibodies. Surprisingly, the stimulus commonly used to induce autoantibodies by blood lymphocytes, Pokeweed mitogen (PWM), inhibits autoantibody synthesis by thyroid lymphocytes. To address this dichotomy, we investigated the Th1: Th2 cytokine balance in relation to thyroid peroxidase (TPO) autoantibody production in cultures of thyroid, lymph node and blood lymphocytes. The characteristic PWM effect on TPO autoantibody production by thyroid and blood lymphocytes (10 day cultures) was confirmed. Cytokine measurements in these cultures revealed that PWM increased IFN-gamma production by thyroid, lymph node and blood lymphocytes. However, PWM enhanced IL-4 levels in lymphocytes from blood and lymph node but not in thyroid lymphocytes. Moreover, the IL-4: IFN-gamma ratios in short- and long-term cultures were higher for PBMC and lymph node lymphocytes than for thyroid lymphocytes. In summary, PWM shifts the cytokine balance towards Th2 for blood lymphocytes and towards Th1 for thyroid lymphocytes. The shift towards Th1 in the target organ is associated with reduced autoantibody synthesis. Our observations suggest that "immune deviation" towards Th2 as a form of therapy in Graves' disease could project the patient from the frying pan into the fire.