The SCID-hu mouse and thyroid autoimmunity: characterization of human thyroid autoantibody secretion.

Severe combined immunodeficient (SCID) mice were injected with peripheral blood mononuclear cells (PBMC) from normal individuals and 14 out of 18 had detectable serum human (h) IgG (maximum levels providing a mean +/- SEM 934 +/- 213 micrograms/ml) and IgM (253 +/- 93 micrograms/ml) at 3-6 weeks after transplantation. Serum human immunoglobulin levels were maximum 6-12 weeks after transplantation and declined to low levels over the subsequent 5 months. Human B cells constituted up to 10% and human T cells up to 40% of cells in the peripheral circulation and spleens of these animals 2-3 weeks after transplantation, PBMC, or intrathyroidal (IT) lymphocytes, from 6 patients with Graves' disease and high serum levels of thyroid autoantibodies were transplanted into 30 SCID mice (Graves' SCID-hu). Although serum human immunoglobulins were observed in only low amounts in the animals receiving IT lymphocytes (n = 4), increased levels of hIgG or hIgM were more easily detectable in 19 Graves' SCID-hu mice that received PBMC. The Graves' SCID-hu mice had significantly lower mean levels of hIgG and hIgM than those observed following transplantation of normal PBMC (mean maximum 328 +/- 113 and 32 +/- 21 micrograms/ml, respectively). Six of these 19 mice had detectable human autoantibody to thyroid peroxidase (TPO, as microsomal antigen) between 3 and 8 weeks after transplantation, with titers ranging from 0.05 to 0.39 (normal SCID-hu serum less than 0.02 ELISA Index). No abnormal thyroid hormone (T4 and T3) levels or thyroiditis was seen when compared to normal SCID-hu mice. Immunization of reconstituted SCID mice with recombinant immunoactive human TPO antigen failed to initiate anti-TPO in normal PBMC-treated mice nor did it increase the titer of human anti-TPO in the anti-TPO positive animals. In conclusion we successfully established human thyroid autoantibody secretion in the SCID-hu mouse and characterized the transient nature of the model. Further studies will be required to achieve successful antigen presentation in this system.