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Effects of Recombinant Human Interleukin-2 and Tumor Necrosis Factor-α with or without Interferon-γ on Human Thyroid Tissues from Patients with Graves' Disease and from Normal Subjects Xenografted into Nude Mice**

1991; Oxford University Press; Volume: 72; Issue: 6 Linguagem: Inglês

10.1210/jcem-72-6-1296

1945-7197

Yoshio Kasuga, Sunao Matsubayashi, F Akasu, Naomi Miller, C Jamieson, Robert J. Volpe,

Thyroid Disorders and Treatments

We have compared the effects of interleukin-2 (IL-2) or tumor necrosis factor-α (TNFα) administration with or without interferon-γ (IFNγ) on Graves' and normal thyroid tissue xenografts in the nude mouse (in the absence of an intact immune system) in terms of possible functional, immunological, or histological changes. The dosages of recombinant human IL- 2, TNFα, and IFNγ given to each mouse were 250, 800, and 4000 U, respectively; they were injected ip daily for 6 consecutive weeks. The parameters measured included the free T4 index, thyroid autoantibodies, and mouse TSH during the course of the study. Thyroid epithelial cell (TEC) HLA-DR expression was measured in thyroid tissue before xenotransplantation and at death; in addition, light microscopic studies were carried out at those times. There were no significant differences in thyroid function between the results in unstimulated (control) animals and those obtained with cytokine administration in either group of tissues, with the exception of the group receiving TNFα together with IFNγ; in this latter group, the free T4 index declined significantly 4–6 weeks after commencement of treatment in the animals with normal thyroid tissue xenografts. The reduction of thyroid function induced by the combination of IFNγ and TNFα observed in normal thyroid tissue may be due to inhibition of thyroperoxidase and thyroglobulin gene transcription. However, there was no such effect on the Graves' thyroid tissue xenografts, perhaps because of down-regulation of this tissue in response to cytokines, after having been released from long term in vivo immune stimulation. On the other hand, TNFα plus IFNγ induced TEC HLA-DR expression on both types of thyroid xenografts at death, although IL-2 alone did not induce HLA-DR expression, and IFNγ induced TEC significantly only on normal thyroid xenografts (but not on Graves' xenografts). In light microscopic examination, Graves' thyroid xenografts treated with IL-2 alone or TNFα plus IFNγ appeared normal at death. In addition, normal thyroid xenografts treated with the same cytokines did not show discernible differences compared to those at human surgery or when the xenografts were untreated at death. We conclude that Graves' TEC did not differ from normal TEC in any significant fashion at the time of death, aside from a reduced responsiveness to the stimuli applied. These observations are again consistent with the previous proposition that Graves' TEC are not unique or abnormal, and may be mere passive captives to immunological events in relation to the pathogenesis of autoimmune thyroid disease.