title: Engraftment of human lymphocytes and thyroid tissue into scid and rag2-deficient mice: absent progression of lymphocytic infiltration.
abstract: To study human autoimmune thyroid disease in an animal model we have investigated the in vivo survival of human thyroid tissues and functionality of human lymphocytes in severe combined immunodeficient (scid) mice and recombination-activating gene (rag2) knockout mice. We found successful engraftment of human thyroid tissues in both scid and rag2-deficient mice. However, when peripheral blood mononuclear cells were transplanted ip, human immunoglobulin production was poor in rag2-deficient mice compared to that in scid mice (mean human immunoglobulin G levels at 6 weeks, 0.2 +/- 0.2 microgram/mL in two of eight rag2-deficient mice compared to 20.8 +/- 7.0 micrograms/mL in seven of nine scid mice; P < 0.05). We, therefore, only pursued the further use of scid mice and transplanted them with thyroid tissue from patients with either Graves' disease (four patients) or Hashimoto's thyroiditis (one patient). At the functional level, we observed transiently increased thyroid hormone levels (T4 peaking at 5.4 +/- 0.2 microgram/dL compared to a normal level of 2.6 +/- 0.2 microgram/dL); human autoantibodies to human thyroglobulin, human thyroid peroxidase, and the human TSH receptor were also detected in thyroid-transplanted mice. In contrast to recent reports, histological examination of the thyroid explants showed no increase in the lymphocytic infiltrate compared to the original donor tissue, nor was there any thyroid follicular destruction observed. In fact, many of the transplants demonstrated a marked diminution in the infiltrates over time, with an absence of HLA-DR antigen expression by both T-cells and thyrocytes. Cotransplanted allogeneic thyroid tissues were unremarkable in terms of lymphocytic infiltrates and showed intact morphology. Taken together, these data point to a relative degree of T-cell inactivity within the thyroid explants from the scid mouse. Hence, a factor(s) present in the patient with autoimmune thyroid disease that activates their thyroid-specific T-cells may be absent in this murine model as presently constructed.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029.
authors.forename: A
authors.initials: A
authors.lastname: Martin
authors.forename: M
authors.initials: M
authors.lastname: Valentine
authors.forename: P
authors.initials: P
authors.lastname: Unger
authors.forename: S W
authors.initials: SW
authors.lastname: Yeung
authors.forename: L D
authors.initials: LD
authors.lastname: Shultz
authors.forename: T F
authors.initials: TF
authors.lastname: Davies
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases; D004268:DNA-Binding Proteins; D006111:Graves Disease / Q000276:immunology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D013959:Thyroid Diseases / Q000276:immunology*; D013961:Thyroid Gland / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D013967:Thyroiditis, Autoimmune / Q000276:immunology
chemical_list: D001323:Autoantibodies; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D009687:Nuclear Proteins; D011506:Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2