EFFECT OF REMOVING HUMAN GRAVES THYROID XENOGRAFTS AFTER 8 WEEKS IN NUDE-MICE AND REXENOGRAFTING THEM INTO SCID MICE

Human thyroid xenografts from four patients with Graves' disease (GD) and two normal persons were initially xenografted into nude mice. Eigh t weeks after xenografting, the thyroid tissue appeared normal; indeed , thyroid infiltrating lymphocytes in the GD xenograft could no longer be identified when analyzed histologically. Thus, human immunoglobuli n G (IgG), thyroperoxidase (TPO)-antibodies (Abs), thyroglobulin (Tg)- Abs, thyroid-stimulating antibodies (TSAb), and thyrocyte histocompati bility leucocyte antigen (HLA)-DR expression were undetectable. These same tissues were retrieved from the nude mouse and rexenografted into severe combined immunodeficient (SCID) mice (with no prior xenograft) ; autologous peripheral blood mononuclear cells (PBMC) or CD8-depleted PBMC (non-CD8 cells) were simultaneously injected into some of these SCID mice. Engraftment of a GD thyroid rexenograft (TH) alone did not cause IgG, TSAb, TPO-Ab, or Tg-Ab production, thyrocyte HLA-DR express ion, or lymphocytic infiltration in thyroid grafts. Engraftment of GD PBMC or non-CD8 cells alone (i.e. without a thyroid xenograft) caused human IgG to rise, but only minimal titers of thyroid antibodies appea red. When TSAb, TPO-Ab, and Tg-Ab were quantified, GD TH plus PBMC-eng rafted SCID mice showed significantly higher production of each antibo dy than that of GD PBMC alone, and this phenomenon was further enhance d by the removal of CD8(+) cells. GD thyrocytes showed marked HLA-DR e xpression at human surgery; however, after 8 weeks' sojourn in nude mi ce, DR expression disappeared. After a further 8 weeks following rexen ografting into SCID mice, TH plus PBMC resulted in a reappearance of D R expression only in GD but not in grafts from normal persons, and thi s was enhanced by the depletion of CD8 cells. These results were also in parallel with histological findings inasmuch as the normal tissue r emained normal with no thyroid antibodies appearing with PBMC or CD8-d epleted cells. In experiments from two GD patients, autologous skeleta l muscle as well as thyroid tissue were xenografted into nude mice. Ei ght weeks after xenografting, these were rexenografted into SCID mice that contained prior autologous primary GD thyroid xenografts. Histolo gical findings showed new lymphocytic infiltration in rexenografted th yroid tissues in the SCID mice but not in autologous skeletal muscle. This signifies that the immune assault in GD is specifically targeted to the thyroid tissue. In conclusion, 1) intrathyroidal lymphocytes fr om primary GD thyroid xenografts in SCID mice migrated to the autologo us second thyroid xenografts (rexenografted from nude mice) but not to autologous skeletal muscle; 2) engraftment of GD PBMC or non-CD8 cell s alone caused human IgG to rise, but thyroid antibodies either did no t appear or were present in low titer; and 3) rexenografted GD thyroid tissue from nude to virgin SCID mice plus autologous PBMC engraftment caused thyroid antibody production and thyrocyte DR expression to ris e. This was further enhanced by the depletion of CD8(+) cells. This an imal model may help to elucidate the pathogenesis of human autoimmune thyroid disease.