title: Pathogenesis of autoimmune hypothyroidism induced by lymphokine-activated killer (LAK) cell therapy: in vitro inhibition of human thyroid function by interleukin-2 in the presence of autologous intrathyroidal lymphocytes.
abstract: Lymphokine-activated killer (LAK) cell therapy frequently results in primary hypothyroidism. To elucidate the responsible mechanism, we investigated the effects of interleukin-2 (IL-2) on thyroid function of cultured human thyroid follicles in the presence or absence of autologous thyroid-derived lymphoid cells (TDLC). Human thyroid follicles, obtained by subtotal thyroidectomy from patients with Graves' disease, were cultured in serum-free medium containing bTSH and various concentrations of human IL-2, with or without TDLC. After 5 days of culture, 125I was added, and after an additional 3 days of culture, 125I incorporated into thyroid follicles and organic 125I (125I-T4 + 125I-T3) released into the culture medium were estimated. In the absence of TDLC, IL-2 did not affect bTSH-induced thyroid function. In the presence of TDLC, however, IL-2 inhibited the bTSH-stimulated thyroid function in a concentration-dependent manner. The minimum IL-2 concentration required to inhibit thyroid function was 1 U/ml. At 100 U/ml, IL-2 inhibited thyroid function completely. IL-2 increased the concentration of IFN-gamma in the culture medium conditioned by TDLC but not by thyroid follicles. When both were cocultured, IL-2 more significantly increased the concentration of IFN-gamma to an extent sufficient for inhibiting thyroid function per se. Furthermore, the addition of anti-IFN-gamma antibody to the medium partially restored the IL-2-inhibited thyroid function. In summary, by coculturing human thyroid follicles and autologous intrathyroidal lymphocytes with IL-2, it was possible to reproduce the thyroid dysfunction associated with LAK cell therapy. Our data indicate that IL-2 inhibits thyroid function, at least partly, by stimulating production of IFN-gamma, a potent inhibitory cytokine for thyroid cells.
authors.affiliation: Department of Medicine, Tokyo Women's Medical College, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: K
authors.initials: K
authors.lastname: Yamazaki
authors.forename: K
authors.initials: K
authors.lastname: Shizume
authors.forename: Y
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: H
authors.initials: H
authors.lastname: Demura
authors.forename: Y
authors.initials: Y
authors.lastname: Kanaji
authors.forename: T
authors.initials: T
authors.lastname: Obara
authors.forename: Y
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: M
authors.initials: M
authors.lastname: Aiba
mesh_terms: D000704:Analysis of Variance; D002450:Cell Communication; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D006111:Graves Disease / Q000503:physiopathology / Q000601:surgery; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000009:adverse effects* / Q000494:pharmacology*; D016209:Interleukin-8 / Q000494:pharmacology; D007454:Iodides / Q000378:metabolism*; D007455:Iodine / Q000378:metabolism; D007457:Iodine Radioisotopes; D015979:Killer Cells, Lymphokine-Activated; D008214:Lymphocytes / Q000502:physiology*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013967:Thyroiditis, Autoimmune / Q000209:etiology* / Q000276:immunology; D013972:Thyrotropin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D007376:Interleukin-2; D016209:Interleukin-8; D007454:Iodides; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013972:Thyrotropin; D007455:Iodine