[A case of type 1 diabetes mellitus in an elderly patient with a history of idiopathic portal hypertension].

The patient is a 71-year-old woman who underwent splenectomy after the diagnosis of idiopathic portal hypertension (IPH) at the age of 51 years. Thirst and polyuria occurred in December 1995. In April 1996, she was hospitalized for assessment because of elevation of her blood glucose and HbA1c levels to 535 mg/dl and 14.9%, respectively. The GAD antibody level was high (256 units/ml) and tests for ICA and anti-TPO antibody were positive. Since her HLA type was A 24, B 13, B 46, CW 1, CW 3, DRB 1*[0901/0901], DQB 1*[0303/0303], and DPB 1*[0201/0201], this patient was regarded as being susceptible to type 1 diabetes mellitus. There was no evidence of portal hypertension at the time of consultation. Although there was a considerable difference in the time of onset between IPH and type I diabetes mellitus, we reported this patient as a valuable case for investigating the complications of autoimmune disease.

Thyroid lymphomas in human thyroid tissue with autoimmune thyroid disease xenografted in severe combined immunodeficient mice.

Malignant lymphoma of the thyroid (MLT) frequently arises in patients with a background of Hashimoto's thyroiditis (HT); however, the mechanisms underlying this chain of events are unknown, and there has been no experimental model. Recently, the development of malignant lymphoma has been reported to occur in peripheral blood lymphocytes engrafted into severe combined immunodeficient (SCID) mice. We xenografted human thyroid tissue from patients with HT or Graves disease (GD) into SCID mice to determine the frequency and nature of MLT in these grafts. Human thyroid tissues ( 12 HT, 1 GD, and 15 from normal [paranodular] tissue) were xenografted into 72 mice (43 mice with HT or GD tissue) within 2 hours after human surgery. Human peripheral blood mononuclear cells (PBMC; 4 autologous HT, I allogeneic HT, and 1 allogeneic GD) were injected intraperitoneally into 6 of the latter 43 mice. In addition, 16 additional SCID mice received normal PBMC injections (alone). The mice were killed 6 to 20 weeks after xenografting. In 4 of 33 SCID mice bearing HT thyroid grafts (without addition of PBMC), MLT developed in the HT graft between 8 and 16 weeks after xenografting. In addition, one spleen of a mouse xenografted with GD tissue alone developed a human malignant lymphoma, although the xenografted thyroid in that mouse did not manifest lymphoma. One additional mouse xenografted with HT thyroid tissue and allogeneic HT PBMC developed malignant lymphoma of both the xenografted thyroid and the mouse spleen. In this mouse, the clonality of these lesions in the two organs was different: the thyroid showed restricted expression of immunoglobulin A (IgA) kappa, whereas the spleen exhibited lambda light chain restriction. One human MLT was removed from a SCID mouse, and equal halves were rexenografted into a nude mouse and another SCID mouse. Thyroid antibodies and IgG levels increased in the second SCID mouse, and the MLT survived; in the nude mouse, however, thyroid antibodies and IgG gradually disappeared, and the MLT regressed, virtually to normal. No MLTs were found in the normal human thyroid xenografts. In SCID mice receiving normal PBMC alone, lymphomas tended to develop when more than 35 x 106 cells were engrafted (a number similar to that of the lymphocytes in the HT xenografts); thus, the MLTs may reflect merely the numbers (and perhaps density) of human lymphocytes present in the xenografts. It is possible that committment of many of the HT-infiltrating lymphocytes to the thyroid might add an additional factor. However, whether this model will prove useful to study the possible transition of HT to MLT remains problematic.

Effects of long-term, high-dose bovine thyrotropin administration on human thyroid tissues from patients with graves' disease and normal subjects xenografted into nude mice.

We have attempted to determine whether the administration of thyrotropin would have any different functional or histological effects on Graves' tissue as opposed to human normal thyroid tissue in an in vivo situation (i.e., after xenograft into nude athymic mice). A dosage of 0.03 units per mouse of bovine thyroid-stimulating hormone (b-TSH) was injected intraperitoneally daily for 6 consecutive weeks into xenografted mice. The parameters measured included the free T4 index and thyroid autoantibodies during the course of b-TSH injections. Tritiated (3H)-thymidine incorporation into thyroid epithelial cells (TECs) and TEC HLA-DR expression were measured in the thyroid tissue at the time of human surgery and at sacrifice; in addition, light-microscopical observations were made at those times. Although there was a decline in free T4 index values during the course of the study, there was light-microscopical evidence suggestive of hyperplasia in both types of xenografted thyroid tissue. The TSH appeared to result in thyrocyte down-regulation, possibly of receptor or postreceptor origin. The administration of the b-TSH seemed to induce TEC HLA-DR expression in this study. Because these results differ from the effects of TSH on TEC in vitro with respect to TEC HLA-DR expression, it may be postulated that there are other factors liberated in vivo in the nude mice that interact with the TEC and TSH and initiate the TEC HLA-DR expression. We conclude that there are no significant differences between the responses of Graves' tissue and the normal human thyroid tissue in these studies.