Kawai K, Enomoto T, Fornasier V, Resetkova E, Volpé R
Endocrinology Research Laboratory, Wellesley Hospital, University of Toronto, Ontario, Canada.
Proc Assoc Am Physicians. 1997 Mar;109(2):126-35.
We have studied the in vivo effects of human interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma) administration on human thyroid tissue xenografted into two mouse strains: severe combined immunodeficient (SCID) mice and nude mice. Human lymphocytes survive in SCID mice but are lysed in nude mice. Thyroid tissues from Graves' disease or Hashimoto's thyroiditis, or paranodular [normal, (N)] tissue was xenografted into SCID mice (0.8 g/mouse) pretreated with anti-asialo GM-1 antiserum and radiation and also into nude mice. One week after xenografting, SCID and nude mice were divided into three groups. Group A was treated with IFN-alpha intraperitoneally (2,000 units/mouse) three times weekly; group B was treated with IFN-gamma similarly; group C was treated with phosphate buffered saline (PBS) only (control). Autologous human peripheral blood mononuclear cells (PBMCs) were added to mice receiving N xenografts. Blood was taken every 2 weeks for levels of IgG and thyroid antibodies (TAb). After 6 weeks of treatment, mice were sacrificed, and xenograft thyrocyte histocompatibility leukocyte antigen (HLA-DR) and intercellular adhesion molecule (ICAM-1) expression were measured. In addition, thyrocyte cultures were stimulated in vitro with 200 units/ml of either IFN-alpha or IFN-gamma or PBS (control). SCID mice xenografted with autoimmune thyroid disease (AITD) in group A showed a significantly higher TAb production than group C, whereas in group B, TAb production was not statistically increased compared to control (group C). SCID mice xenografted with N did not produce TAb in any group, nor did nude mice xenografted with AITD. Thyrocyte HLA-DR expression was markedly increased in group A and B in SCID mice xenografted with Graves' disease, Hashimoto's thyroiditis, and N tissue compared to group C. In contrast, only group B (IFN-gamma) showed an increase in thyrocyte HLA-DR in nude mice. In the in vitro studies, only IFN-gamma (not IFN-alpha) stimulated thyrocyte HLA-DR and ICAM-1 expression in Graves' disease, Hashimoto's thyroiditis, and N tissues. We concluded that in SCID mice, IFN-alpha causes TAB production in AITD xenografts but not in N xenografts, while increasing thyrocyte HLA-DR expression in both. Also, IFN-gamma does not cause a statistically increased TAb in AITD xenografts in SCID mice, despite a sharp rise in thyrocyte HLA-DR expression. In addition, because IFN-alpha has no effect in nude mice or in vitro on thyrocyte HLA-DR expression, its effects in SCID mice must be mediated via local infiltrating lymphocytes. Finally, IFN-gamma has a direct effect on thyrocytes to increase HLA-DR expression (and, in vitro, ICAM-1 expression) but may not stimulate TAb production.
我们研究了给予人α干扰素（IFN-α）和γ干扰素（IFN-γ）对移植到两种小鼠品系中的人甲状腺组织的体内作用：严重联合免疫缺陷（SCID）小鼠和裸鼠。人淋巴细胞在SCID小鼠中存活，但在裸鼠中被裂解。将来自格雷夫斯病或桥本甲状腺炎的甲状腺组织，或结节旁[正常，（N）]组织移植到用抗唾液酸GM-1抗血清和辐射预处理的SCID小鼠（0.8克/只）以及裸鼠中。移植后一周，将SCID和裸鼠分为三组。A组每周三次腹腔注射IFN-α（2000单位/只）；B组以类似方式用IFN-γ治疗；C组仅用磷酸盐缓冲盐水（PBS）治疗（对照）。将自体人外周血单核细胞（PBMC）添加到接受N移植的小鼠中。每2周取血检测IgG和甲状腺抗体（TAb）水平。治疗6周后，处死小鼠，检测移植甲状腺细胞的组织相容性白细胞抗原（HLA-DR）和细胞间黏附分子（ICAM-1）表达。此外，用200单位/毫升的IFN-α或IFN-γ或PBS（对照）体外刺激甲状腺细胞培养物。A组移植自身免疫性甲状腺疾病（AITD）的SCID小鼠TAb产生显著高于C组，而B组与对照组（C组）相比，TAb产生无统计学意义的增加。移植N的SCID小鼠在任何组中均未产生TAb，移植AITD的裸鼠也未产生。与C组相比，移植格雷夫斯病、桥本甲状腺炎和N组织的SCID小鼠中，A组和B组甲状腺细胞HLA-DR表达明显增加。相反，仅B组（IFN-γ）在裸鼠中显示甲状腺细胞HLA-DR增加。在体外研究中，仅IFN-γ（而非IFN-α）刺激格雷夫斯病、桥本甲状腺炎和N组织中的甲状腺细胞HLA-DR和ICAM-1表达。我们得出结论，在SCID小鼠中，IFN-α导致AITD移植组织中产生TAb，但在N移植组织中不产生，同时增加两者的甲状腺细胞HLA-DR表达。此外，尽管甲状腺细胞HLA-DR表达急剧上升，但IFN-γ在SCID小鼠的AITD移植组织中未导致TAb产生有统计学意义的增加。另外，由于IFN-α对裸鼠或体外甲状腺细胞HLA-DR表达无影响，其在SCID小鼠中的作用必定通过局部浸润淋巴细胞介导。最后，IFN-γ对甲状腺细胞有直接作用以增加HLA-DR表达（以及在体外增加ICAM-1表达），但可能不刺激TAb产生。
