EFFECT OF FK-506 ON XENOGRAFTED HUMAN GRAVES THYROID-TISSUE IN SEVERECOMBINED IMMUNODEFICIENT MICE

OBJECTIVE We studied the macrolide antibiotic FK-506, an immunosuppres sive agent, in an attempt to ameliorate the lesion of autoimmune thyro id disease in human thyroid tissue xenografted into severe combined im munodeficient (SCID) mice. It was not felt appropriate to employ this agent directly in patients with autoimmune thyroid disease because ade quate therapeutic modalities are available and the introduction of new , experimental agents could not be justified. Moreover, the study of t he tissue before and after treatment could not have been undertaken di rectly in patients. DESIGN Human thyroid xenografts from four patients with Graves' disease and two normal persons were xenografted into SCI D mice. Two weeks after xenografting, human immunoglobulin G (IgG) was detectable in all SCID mice xenografted with Graves' thyroid tissue. Mice were divided into two groups with human IgG levels similar to eac h other. Mice in the first group were treated with FK-506 daily for 6 weeks; mice in the second (similar) group were given phosphate-buffere d saline (PBS) only (control group). MEASUREMENTS Blood samples were t aken every 2 weeks from the tail veins for human IgG, thyroid stimulat ing antibody, thyroperoxidase antibodies, thyroglobulin antibodies, an d interferon-gamma (IFN-gamma). After 8 weeks treatment, animals were sacrificed; thyroid tissue was examined histologically and for thyrocy te HLA-DR expression. FK-506 was also added to thyrocytes in in-vitro tissue culture conditions. RESULTS After 4-6 weeks of FK-506 therapy, human IgG, all thyroid antibodies and IFN-gamma were suppressed, while the levels remained elevated in the control group. Lymphocytic infilt ration virtually disappeared in the human thyroid tissue of the FK-506 -treated mice and thyrocyte HLA-DR expression markedly declined; in th e control mice, lymphocytic infiltration remained heavy and HLA-DR exp ression remained high. On the other hand, FK-506 added directly to thy rocytes in vitro (without lymphocytes) did not reduce thyrocyte HLA-DR expression. CONCLUSIONS FK-506 appears to suppress the activation of intrathyroidal lymphocytes, but not thyrocytes. From these observation s, it is concluded that this agent, by its action on intrathyroidal ly mphocytes, is able to ameliorate the immunologically mediated histolog ical and serological disturbance in human autoimmune thyroid disease, at least under these circumstances.