Rapidly progressive thyroid failure in Graves' disease after painful attack in the thyroid gland.

We studied a new type of Graves' disease: rapidly progressive thyroid failure after painful attack in the thyroid gland. Four women with the mean (+/- SD) age of 51 +/- 3.2 years had newly diagnosed hyperthyroid Graves' disease. A severe painful episode developed in the thyroid glands of two patients and permanent hypothyroidism occurred spontaneously within 2 or 3 months thereafter. Two to three episodes of pain developed in the thyroid glands of the other two patients during antithyroid drug therapy. There was a transient rise in serum thyrotropin level after each painful episode and permanent hypothyroidism developed 6 to 8 months after the initial painful attack. The clinical picture is characterized by moderate to severe pain in the thyroid gland with tenderness. Patients responded to steroid or anti-inflammatory therapy. During painful attack, increased or normal thyroid radioiodine uptake, elevated levels of C-reactive protein, and an elevated erythrocyte sedimentation rate were found, but there was no cytological evidence of subacute thyroiditis. After painful attack, serum thyroid stimulation antibody began to decrease in three of the patients while thyroid stimulation blocking antibody developed in one patient. This is a rapid and self-destructive process of the Graves' thyroid gland, which appears to be associated with painful attack in the thyroid gland.

Clinical characteristics of subacute thyroiditis classified according to human leukocyte antigen typing.

We investigated human leukocyte antigen (HLA) class I and class II antigens in 56 Japanese patients with subacute thyroiditis (SAT) who visited our out-patient clinic between 1988 and 1990. We found SAT to be associated with not only HLA-B35 (40 patients; P < 0.000001; relative risk, 18.02), but also with HLA-B67 antigens (9 patients; P < 0.00001; relative risk, 11.20). No heterozygotes of HLA-B35 or HLA-B67 were found in any of the 56 patients with SAT. Either HLA-B35 or HLA-B67 antigen is found in 87% of patients with SAT. When season of onset and clinical course of SAT were compared in the 49 patients with HLA-B35-positive SAT (B35-SAT) and HLA-B67-positive SAT (B67-SAT), we were able to identify certain characteristics: 1) B67-SAT often followed the course from transient thyrotoxicosis to a hypothyroid phase to a euthyroid phase [6 of 9 B67-SAT (67%) vs. 10 of 40 B35-SAT (25%); P < 0.05]; and 2) B67-SAT occurred mostly during the summer or autumn and at a higher rate than did B35-SAR [8 of 9 B67-SAT (89%) vs. 17 of 40 B35-SAT (43%)], whereas B35-SAT occurred throughout the year. We conclude that there are at least two types of SAT that can be classified by association with either HLA-B35 or HLA-B67 antigens.

The occurrence of thyrotropin binding-inhibiting immunoglobulins and thyroid-stimulating antibodies in patients with silent thyroiditis.

Silent (painless) thyroiditis has been recognized as a clinical entity for over a decade and is characterized by spontaneously resolving thyrotoxicosis. Its etiology is uncertain; however, a few reports have indicated the occurrence of TSH binding-inhibiting immunoglobulins (TBII) and thyroid-stimulating antibodies (TSAb) in some of the patients. The present study was undertaken to evaluate thyroid function and the occurrence of TBII and TSAb and thyroid autoantibodies (antithyroglobulin and antimicrosomal) in 53 patients with silent thyroiditis during the course of their disease. The patients were divided into 2 major groups: I) those who developed transient hypothyroidism and II) those who did not. All patients initially had significantly increased concentrations of serum T4, free T4, and free T3, suppressed TSH levels, and decreased thyroid radioiodine uptake. TBII and TSAb were initially positive in 8 (15.1%) and 10 patients (18.9%), respectively. Forty patients were available for follow-up. TBII was positive in 6 of 24 (25.0%), and TSAb was positive in 8 of 24 (33.3%) of the patients who developed transient hypothyroidism during the course of their disease. Among the patients who did not become hypothyroid at any time, TBII was positive in only 2 of 16 (12.5%), and none of the patients became TSAb positive. The findings indicate that increased TSAb and TBII activity may be detected in patients with silent thyroiditis and, when present, are associated with transient hypothyroidism during the course of the disease.

The incidence of thyroid stimulating blocking antibodies during the hypothyroid phase in patients with subacute thyroiditis.

The etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. It has been suggested that nonimmune processes are involved in SAT patients who have negative autoantibody titers. The disease has a variable course; although it is self-limited in most cases, some patients develop transient hypothyroidism, and others do not during the recovery period. The present study was performed to evaluate the occurrence of TSH receptor antibody (TRAb), measured by RRA (TSH binding inhibitor), TRAb measured by stimulation assay (thyroid-stimulating antibody), and TRAb measured by blocking assay [TSH-blocking antibody (TSH-BAb)] activity in 68 patients with SAT who had negative autoantibody titers. The patients were divided into 2 groups: group I, 31 patients who developed hypothyroidism during the recovery period; and group II, 37 patients who remained euthyroid during recovery. Positive immunoglobulin activity occurred in about 20% of group I patients during follow-up, but in only 3% of group II patients. About 20% of group I patients developed positive TSH-BAb activity and were hypothyroid, requiring exogenous hormone therapy for 1.2-3.5 yr, whereas hypothyroidism was relatively transient in group I patients who had negative TSH-BAb activity (2-6 months). Although increased TSH-BAb activity may account for hypothyroidism in some patients with SAT, the precise mechanism for the development of transient hypothyroidism in SAT remains enigmatic.

The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland.

Ninety-five patients with papillary thyroid carcinoma (PTC) who received primary surgical treatment in 1983 at Kuma Hospital and were followed until 1992 were the subjects of this study. Initial therapy was tumor resection for 5 patients, lobectomy for 23 patients, total thyroidectomy with unilateral modified neck dissection for 60 patients, and total thyroidectomy with bilateral modified neck dissection for 7 patients. Clinical stage at diagnosis was as follows. Class I included 28 patients with intrathyroidal disease, class II included 60 patients with positive cervical lymph nodes, and class II included 7 patients with tumor invasion into tissue outside of the thyroid gland. Recurrence of the tumor was evaluated according to lymphocytic infiltration in the thyroid gland. Group A consisted of 36 patients with PTC associated with lymphocytic infiltration, 26 with infiltration surrounding the tumor, 3 with infiltration inside of the tumor, and 7 with both. Group B consisted of the remaining 59 patients with PTC with no lymphocytic infiltration. There were no differences in age, sex, initial tumor size, or initial treatment between groups A and B. Antithyroglobulin antibody and/or antimicrosomal antibody were positive in 16 patients from group A and 4 patients from group B (P < 0.001). Class I included 14 patients from each group, class II included 22 patients from group A and 38 patients from group B, and class III included 7 patients, all from group B. Recurrence of the tumor was found in only 1 group A patient (2.8%), but in 11 patients of group B (18.6%). The percentage of patients free from recurrence over the 10 yr of follow-up in group A was significantly higher than that in group B (by Cox-Mantel test, P < 0.01). The time between initial treatment and recurrence was 2-10 yr. In comparing the clinical stage at the time of initial treatment, recurrence was found in 1 class II patient from group A (4.5%) and in 1 class I (7.1%), 6 class II (15.8%), and 4 class III (57.1%) patients from group B. No patients died during the 10 yr of follow-up. In conclusion, 1) lymphocytic infiltration surrounding the tumor or inside the tumor in PTC might be of use as a means for predicting a favorable prognosis; and 2) class II or class III patients with no lymphocytic infiltration had a high rate of recurrence.

Expression of intercellular adhesion molecule-1 on human thyroid cells from patients with autoimmune thyroid disease: study of thyroid xenografts in nude and severe combined immunodeficient mice and treatment with FK-506.

It has been suggested that intercellular adhesion molecule-1 (ICAM-1) may play an important role in the initiation, localization, and perpetuation of autoimmune thyroid diseases (AITD). In an effort to clarify its role, we have investigated the expression of ICAM-1 on thyroid epithelial cells (TEC) of patients with AITD, patients with nontoxic goiter (NTG), and normal subjects (PN) by flow cytometric analysis under basal conditions and after modulation with cytokines, before and after 8 weeks of thyroid tissue xenotransplantation in nude athymic mice (which lyses all passenger lymphocytes), and in severe combined immunodeficient (SCID) mice where these cells survive. Before xenografting, ICAM-1 was expressed on 56% of TEC from Hashimoto's thyroiditis (n = 5), 54% of Graves' disease (n = 6), 15% of NTG (n = 5), and 12% of PN TEC. After the xenografts had been 8 weeks in nude mice, ICAM-1 expression decreased markedly in AITD TEC [from 56% to 10% in Hashimoto's thyroiditis (P < 0.001) and from 54% to 8% in Graves' disease (P < 0.01)], but did not change significantly in NTG or PN. After the xenografts had been 8 weeks in SCID mice, the expression of ICAM-1 was significantly higher on TEC of AITD compared with the same tissue in nude mice. When the SCID mice engrafted with AITD tissue were treated with the anti-CD4+ T (helper) cell agent FK-506, the expression of ICAM-1 was reduced significantly compared with that in the original tissue or that in nontreated mice engrafted with the same tissue. The proportion of TEC that were ICAM-1 positive was up-regulated in all cases by certain cytokines (e.g. interferon-gamma and tumor necrosis factor-alpha applied alone or in combination). We also detected the presence of ICAM-1 in AITD frozen tissues using an immunohistochemical technique. These data suggest a role for ICAM-1 in human AITD. However, the expression of ICAM-1 appears to be a secondary phenomenon in response to the immune assault, rather than a primary event. Our results support the idea that TEC may act as passive captives to immunological events in human AITD.

Effect of removing human Graves' thyroid xenografts after eight 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. Eight 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 immunoglobulin G (IgG), thyroperoxidase (TPO)-antibodies (Abs), thyroglobulin (Tg)-Abs, thyroid-stimulating antibodies (TSAb), and thyrocyte histocompatibility 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 expression, 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 appeared. When TSAb, TPO-Ab, and Tg-Ab were quantified, GD TH plus PBMC-engrafted SCID mice showed significantly higher production of each antibody than that of GD PBMC alone, and this phenomenon was further enhanced by the removal of CD8+ cells. GD thyrocytes showed marked HLA-DR expression at human surgery; however, after 8 weeks' sojourn in nude mice, DR expression disappeared. After a further 8 weeks following rexenografting into SCID mice, TH plus PBMC resulted in a reappearance of DR expression only in GD but not in grafts from normal persons, and this was enhanced by the depletion of CD8 cells. These results were also in parallel with histological findings inasmuch as the normal tissue remained normal with no thyroid antibodies appearing with PBMC or CD8-depleted cells. In experiments from two GD patients, autologous skeletal muscle as well as thyroid tissue were xenografted into nude mice. Eight weeks after xenografting, these were rexenografted into SCID mice that contained prior autologous primary GD thyroid xenografts. Histological findings showed new lymphocytic infiltration in rexenografted thyroid 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.(ABSTRACT TRUNCATED AT 400 WORDS)

Activation of T lymphocyte subsets by synthetic TSH receptor peptides and recombinant glutamate decarboxylase in autoimmune thyroid disease and insulin-dependent diabetes.

We have postulated that a defect in specific antigenic induction of suppressor T lymphocytes may account for the immunoregulatory disorder in autoimmune thyroid disease. In this context, we have measured the proliferative responses of peripheral blood mononuclear cells (PBMC) to the synthetic peptides corresponding to the extracellular domain of the TSH receptor (TSHR) and recombinant glutamate decarboxylase (GAD65) by means of 3H thymidine incorporation. We have also studied the antigenic activation of CD4+ and CD8+ T lymphocytes by measuring human leukocyte antigen-DR (HLA-DR) expression on the cell surface by flow cytometric analysis. PBMC obtained from 47 patients with Graves' disease (GD) [including 19 hyperthyroid GD (hyper GD)], 18 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), 18 with insulin-dependent diabetes (IDDM), and 20 normal controls (N), were cultured for 7 days in the presence or absence of the pool peptides representing 3 different segments of TSHR or GAD65 at final concentration of 30 micrograms/mL or 10 micrograms/mL. The proportion of subjects whose PBMC gave a positive proliferative response with a stimulation index (SI) of over 2.3 (i.e. above the mean +2 SD for N) to TSHR peptides was significantly higher in the hyper GD group than among euthyroid GD (eu GD), HT, IDDM, and N group. The corresponding differences in mean SI provided analogous results, showing significant responses above normal in only hyper GD. The CD4+ T lymphocytes from hyper GD group were significantly more activated by TSHR peptides compared to eu GD, HT, IDDM, and N, and this induction correlated to their thyroid hormone levels. Quite differently, the activation of CD8+ T lymphocytes from both hyper GD and eu GD group in response to TSHR peptides was impaired compared to HT, IDDM, and the N group; in contrast to the findings with CD4+ T lymphocytes, this was independent of thyroid hormone levels. On the other hand, while the CD8+ T lymphocytes from GD and N groups were activated equally by GAD65, the activation of CD8+ T lymphocytes from the IDDM group by GAD65 was impaired compared to the GD and N groups. In conclusion, the activation of CD8+ T lymphocytes from GD and IDDM by relevant antigens (i.e. TSHR peptides for GD and GAD65 for IDDM) was impaired, but not by irrelevant antigens (i.e. GAD65 for GD and TSHR peptides for IDDM). There was also a modest stimulation of CD8+ T cells from all groups by tetanus toxoid and cardiac myosin light chain peptide, both irrelevant antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF).

Agranulocytosis, although extremely infrequent, is a serious complication of antithyroidal drug therapy in patients with hyperthyroidism. Presently, there is no specific therapy for this life-threatening complication, and recovery time is highly variable. Recently, recombinant human granulocyte colony-stimulating factor (rhG-CSF) was reported to be effective in shortening the recovery time of the neutropenia in patients undergoing chemotherapy. The present study was undertaken to determine the efficacy of rhG-CSF administration in patients with methimazole-induced (MMI) agranulocytosis. Thirty-four patients (7 males and 27 females, ages 16-68 yr) with MMI agranulocytosis were divided into 3 groups: group A (n = 11) was treated with antibiotics only; group B (n = 11) received antibiotics and dexamethasone, 8 mg/day; and group C (n = 12) was treated with antibiotics and im injections of rhG-CSF, 75 micrograms/day. Patients in groups A and B were studied retrospectively. When rhG-CSF became available, patients in group C were studied prospectively. Bone marrow sternal punctures were performed in all group C patients who were then divided into 2 subgroups according to the granulocyte to erythrocyte count ratio (G:E). Group C1 (n = 6) had a G:E ratio of less than 0.5, and group C2 (n = 6) had a ratio of more than or equal to 0.5. Recovery time in all groups was defined as the number of days required for the peripheral granulocyte count to be greater than 1.0 x 10(9)/L. There was no significant difference in recovery time between groups A and B: 10.1 +/- 2.2 and 12.3 +/- 1.9 days (mean +/- SE), respectively. P was not significant; the administration of dexamethasone proved to be ineffective in shortening the time for recovery from peripheral granulocytes. On the other hand, recovery time was significantly shorter in group C (6.8 +/- 1.2 days mean +/- SE) compared with groups A and B (P < 0.05). Group C2 recovered in 2.2 +/- 0.6 days whereas group C1 took much longer, 9.8 +/- 1.3 days (P < 0.001). There was a direct correlation between the G:E ratio and the peripheral leucocyte count, r = 0.806, P < 0.01. Furthermore, rhG-CSF significantly shortened recovery time when the peripheral granulocyte count was greater than 0.1 x 10(9)/L (group C2) compared with patients whose counts were less than 0.1 x 10(9)/L (group C1), 2.2 +/- 0.4 vs. 8.6 +/- 1.3 days, respectively (P < 0.001). These data indicate that administration of steroids is ineffective in shortening the duration of recovery in patients with MMI agranulocytosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Responses of growth hormone and cortisol to intravenous glucose loading test in patients with anorexia nervosa.

The hypothalamic satiety and hunger centers appear to be affected by changes in circulating blood glucose concentrations. The response of the centers, in turn, is reflected by alterations in growth hormone (GH) and cortisol levels. There are no studies attempting to relate blood glucose and GH and cortisol changes in patients with anorexia nervosa (AN) during an intravenous glucose tolerance test (IVGTT). In the present inquiry, IVGTT (10 g) were performed on AN patients to characterize the satiety and hunger centers' responses to changes in glucose and insulin levels as reflected by GH and cortisol levels. Study participants were 15 female AN patients and eight healthy female volunteers. No significant differences in blood glucose levels were observed between the two groups. However, immunoreactive insulin (IRI) levels in AN patients were significantly lower than those in the control group. Although GH and cortisol concentrations were significantly suppressed after the infusion in the control group, the AN patients' GH levels paradoxically increased, and cortisol levels did not change. Moreover, a negative correlation was observed between delta GH and delta IRI in all individuals in this study (r = -.61, P less than .01). In conclusion, abnormal GH and cortisol responses to a 10-g IVGTT were found in patients with AN. delta GH levels correlated negatively with delta IRI levels. These data suggest that hypothalamic satiety and hunger centers in AN respond abnormally to change in blood glucose levels.

The effect of adding a surfeit of autologous CD8+ T cells to SCID mice after secondary rexenografts of Graves' thyroid tissue.

To investigate the effect of adding a surfeit of CD8+ T cells as a potential immunoregulator in Graves' disease (GD), thyroid tissues from 4 patients with GD and 2 normal subjects (N) were initially xenografted into nude mice. Eight weeks after xenografting, the thyroid tissues, which were then devoid of lymphocytes and appeared normal, were retrieved from the nude mouse, and rexenografted (rexenografts) into severe combined immuno-deficient (SCID) mice; 20 x 10(6) of autologous peripheral blood mononuclear cells (PMBC) or 20 x 10(6) of CD8(+)-depleted PBMC ("non-CD8 cells," i.e., CD4-enriched PBMC) were simultaneously engrafted into SCID mice with thyroid rexenografts. In addition, 20 x 10(6) of CD8(+)-enriched PBMC ("CD8-doubled" cells, which were prepared to double the percentage of CD8+ T cells compared to that of PBMC) were engrafted into SCID mice with rexenografts from 2 GD and 2 N; finally, 20 x 10(6) of PBMC plus an extra 10 x 10(6) of CD8+ T cells ("extra-CD8 added" cells, total 30 x 10(6) of CD8-enriched cells) were engrafted into separate SCID mice with rexenografts from 2 GD. The reengraftment of GD rexenografts or N rexenografts alone did not result in the detection of thyroperoxidase (TPO)-antibodies (Abs), thyroglobulin (Tg)-Abs, thyroid-stimulating Ab (TSAb) production, human IgG, or lymphocytic infiltration in the xenografts. However, the engraftment of either autologous PBMC or non-CD8 cells from patients with GD and N into SCID mice with rexenografts caused human IgG to become detectable and then rise further in 10 of 17 SCID mice; when human IgG, TPO-Ab, Tg-Ab, and TSAb were quantitated, GD rexenografts plus non-CD8 cells engrafted into SCID mice showed a higher production of each antibody and human IgG than in GD rexenografts plus PBMC, or GD rexenografts plus CD8-doubled cells, or GD rexenografts plus extra "CD8-added" cells. Moreover, when CD8-doubled cells or extra CD8-added cells with rexenografts were engrafted to SCID mice with rexenografts, they showed generally lower production of human IgG and thyroid antibodies compared to SCID mice into which PBMC were engrafted with rexenografts, despite the fact that 50% more cells (30 x 10(6)) were engrafted in the preparations of extra CD8-added cells. In conclusion, CD8+ T cells from patients with GD appeared to suppress the induction of thyroid antibodies, TSAb, and human IgG. The CD8+ cells thus are acting as suppressor or regulatory T cells. Such cells might be important in the pathogenesis of autoimmune thyroid disease.

Homing of 51Cr-labeled human peripheral lymphocytes to Graves' thyroid tissue xenografted into SCID mice.

We have recently described a NUDE/SCID mouse model that has been useful for the study of human thyroid autoimmunity in in vivo conditions. The reappearance of lymphocytic infiltration in Graves' thyroid tissue and a humoral response in SCID mice (rexenografted with normalized thyroid tissues from NUDE mice) was detected only if autologous Graves' human peripheral lymphocytes (PBMC) were engrafted into the same animals. Therefore it was presumed that some autoreactive PBMC directed themselves to the thyroid. However, there was previously no direct evidence regarding the trafficking of the engrafted PBMC to the target tissue. To elucidate this point we have studied the migration of 51Cr-labeled PBMC in SCID mice. Human thyroid tissue from six Graves' disease (GD) patients and six patients with nontoxic nodular goiter were initially xenografted into NUDE mice for 8 weeks. The same tissues were retrieved and rexenografted into several "virgin" SCID mice, i.e., no previous xenografts. Autologous PBMC were isolated from blood of the same patients obtained at the time of the tissue rexenograftment and labeled with radioactive 51Cr. Twenty million labeled PBMC were engrafted into each SCID mouse. The distribution of labeled lymphocytes into mouse organs and trafficking into Graves' and normal xenografts was measured. A significant amount of radioactivity in Graves' xenografts was detected after 1 week with the peak of radioactivity at 2-3 weeks. This radioactivity was significantly higher than radioactivity in surrounding tissues (skin, muscle). In contrast, homing of autologous lymphocytes into normal paranodular thyroid tissue was very minimal; the radioactivity of GD thyroid xenografts with engrafted autologous lymphocytes was significantly higher than that of normal tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Seroreactivity to bacterial antigens is not a unique phenomenon in patients with autoimmune thyroid diseases in Canada.

It has been suggested elsewhere that the enteric pathogen Yersinia enterocolitica (Y.e.) might be implicated etiologically in autoimmune thyroid disease (AITD). To reevaluate this hypothesis in the Canadian population, where the prevalence of anti-Y.e. antibodies in the general population is very low (< 1%), we have studied the occurrence of antibacterial reactivity (against Y.e. 0:3 and 0:9, Escherichia coli and Staphylococcus aureus) in the sera of patients with Hashimoto's thyroiditis (HT), Graves' disease (GD), nontoxic nodular goiter (NTG), and autoimmune rheumatic diseases (ARD) as well as normal controls (C). Using the tube agglutination method, no single positive sample was detected in these subjects. No differences in the mean levels of anti-Y.e. 0:3 or 0:9 by ELISA were observed between various groups of patients. Immunoreactivity in the course of medical therapy during 5-12 months did not show significant changes in any of 12 ARD and AITD patients. Some serological reactivity to the plasmid containing strain of Y.e. 0:3 was demonstrated in all subjects by the Western blotting technique. However, weaker signals and fewer bands were noticed in these sera compared to sera from patients with acute yersiniosis. Analysis of the pattern of reactivity did not show any difference in reactivity to any protein between the groups of subjects. The immunodominant antigen in Y.e. 0:3 to which IgG reacted in almost all subjects was the plasmid encoded 240-kDa protein. Our study favors the view that there is a merely coincidental incidence of seroreactivity to bacterial antigens, which appears to be irrespective of diagnosis.

Studies of human thyroid xenografts from Hashimoto's thyroiditis in severe combined immunodeficient (SCID) mice: detection of thyroid stimulation-blocking antibody.

Human thyroid xenografts from 7 patients with Hashimoto's thyroiditis (HT) and 3 normal persons (N) were xenografted into severe combined immunodeficient (SCID) mice to study the intrathyroidal lymphocytes that were expected to survive in these animals. Human IgG was detected in all mice engrafted with HT thyroid tissue peaking at 6-10 weeks after xenografting. Thyroperoxidase-antibody (TPO-Ab) was also detected in all mice with HT thyroid grafts peaking at 4-6 weeks after xenografting, reaching up to 44% of donors' original concentrations. In contrast, maximal thyroglobulin (Tg)-Ab production in some SCID mice with HT thyroid grafts was higher than the donors' original level, and was detectable in mice with thyroid grafts from Tg-Ab-negative HT donors. Thyroid stimulation-blocking antibody (TSBAb) was found in 2 mice with thyroid xenografts from 1 HT patient whose original serum TSBAb and thyrotropin-binding inhibitor immunoglobulin (TBII) had been positive; the maximal TSBAb level in SCID mice exceeded the donor's original level. TSBAb production in SCID mice reached its peak at 10 weeks after xenografting, i.e., later than that of thyroid-stimulating antibody (TSAb) observed in our recent report, suggesting the existence of distinct intrathyroidal B cell autoreactive clones of different life span responsible for secreting TSAb or TSBAb. When autologous peripheral blood mononuclear cells (PBMC) were engrafted alone (without thyroid tissue), TSBAb was undetectable.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of monoclonal antibody against CD45RB on peripheral blood mononuclear cell proliferation and on HLA-DR and adhesion molecule expression on thyrocytes of patients with autoimmune thyroid disease.

To evaluate the role of CD45 (especially that of the ectodomain region B) on immunocyte-thyrocyte signaling in patients with autoimmune thyroid disease (AITD), we have examined the in vitro and in vivo effects of a monoclonal antibody (mAb) against with CD45RB, termed MT3. MT3 was added to cultured peripheral blood mononuclear cells (PBMC) from patients with AITD and was additionally injected into severe combined immunodeficient (SCID) mice to which Graves' thyroid cells and intrathyroidal lymphocytes were engrafted. MT3 stimulated proliferation of PBMC when cultured for 2 to 3 days in patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD) and in normal controls (NC). However, when cultured for 7 days, the stimulation index [SI: counts per minute (cpm) with mAb/cpm without mAb] was lowered by MT3 in NC and GD patients. However, the mean SI was not lowered in patients with HT. In SCID mice, the concentrations of human immunoglobulin G, antithyroglobulin and antithyroperoxidase antibodies in sera were not significantly changed by injecting MT3. The expression of human leukocyte antigen (HLA)-DR and intercellular adhesion molecule (ICAM)-1 on engrafted human thyrocytes decreased after the tissues were engrafted into the control mice to which vehicle alone was injected. However, in the mice injected with MT3, HLA-DR and ICAM-1 expression remained high or up-regulated by the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of chemotherapy for advanced adenocarcinoma of the pancreas in combined modality therapy.

Because it is difficult to diagnose at an early stage, pancreatic carcinoma is usually well advanced by the time it is diagnosed. The combined use of intraoperative radiotherapy, gastrointestinal and/or biliary tract bypass operation, celiac plexus nerve block, and chemotherapy is widely applied in treatment, with favorable results reported in some patients with advanced disease. To evaluate the efficacy of chemotherapy in such combinations, we compared the effect of 5-fluorouracil, its analogues, and mitomycin C on the survival of patients with advanced stage pancreatic cancer. We found no significant difference between the patients treated or not treated with these drugs. Clearly, there is a need for new agents having greater efficacy against pancreatic carcinoma.

The role of thyroid stimulating antibody (TSAb) in the thyroid function of patients with post-partum hypothyroidism.

OBJECTIVE: We investigated the association between thyroid function and the biological activities of thyroid stimulating antibodies (TSAb) and thyroid stimulation blocking antibodies (TSBAb) in patients with post-partum hypothyroidism. DESIGN: A prospective study. PATIENTS: We studied 25 patients with post-partum hypothyroidism who visited our thyroid clinic during the period from 1985 to 1990. MEASUREMENTS: We measured TSH binding inhibitory immunoglobulin (TBII) and TSAb activity at the initial presentation of each of the 25 patients. Women found to have elevated TSAb activity were followed up. Upon finding negative TSAb activity along with positive TBII activity in the serum at the initial presentation, we measured TSBAb activity. Women found to have elevated levels of TSBAb at the initial presentation were also followed up. RESULTS: Elevated TBII activity was found in six of the 25 patients, as was high TSAb activity (205-2651%, normal 55.0-145.0%) in five of these six and in one other patient at the initial presentation. Markedly elevated TSBAb activity (89%) was found in one TBII positive patient. We were able to follow up serially five TSAb positive patients and the TSBAb positive patient over periods ranging from 11.5 to 26.5 months post-partum. The maximal value of TSAb activity was observed at the initial presentation in all TSAb positive patients, following which the activities gradually decreased. One of these patients developed Graves' hyperthyroidism associated with high TSAb activity (1223%) at 10.5 months post-partum. One of the other patients was restored to euthyroid with elevated TSAb activity (279%), but thereafter developed hypothyroidism in conjunction with the disappearance of TSAb activity at 26.5 months post-partum. In the other two patients, normalization of thyroid function was observed with elevated TSAb activity. Thereafter, thyroid function remained within the normal range even with the disappearance of TSAb activity. In the other patient, normalization of thyroid function was observed at 11.5 months post-partum, 3 months after the disappearance of TSAb activity. In the TSBAb positive patient, TSBAb activity decreased to 21% by 17.5 months post-partum associated with normalization of thyroid function. CONCLUSION: The present study demonstrates the presence of elevated levels of TSAb activity in some patients with post-partum hypothyroidism. In these patients, Graves' hyperthyroidism may be induced by TSAb activity, and hypothyroidism may reoccur with the disappearance of the TSAb activity. Furthermore, post-partum hypothyroidism may be due to increased TSBAb activity in some patients.

A follow-up study of 85 patients with Graves' disease in remission who developed undetectable serum thyroid-stimulating hormone concentrations using sensitive TSH assays.

Eighty-five patients with Graves' disease in clinical remission after treatment for over 1 year by methimazole therapy (36 patients, group A) or subtotal thyroidectomy (49 patients, group B) who became undetectable for serum thyrotropin levels (TSH less than 0.05 mU/l), were further followed for 1 year or more. Eight patients in group A (22%) and 7 patients in group B (14%) relapsed. Eleven patients in group A (30%) and 5 patients in group B (10%) had fluctuating patterns of free T4 in the upper normal to slightly supranormal range indicative of subclinical hyperthyroidism. The remaining patients continued to have undetectable TSH levels or restored normal TSH levels and normal thyroid hormone concentrations in sera. The results of the present study indicate that the occurrence of undetectable serum TSH concentrations in Graves' disease patients previously treated with methimazole or surgery are not necessarily predictive of clinical relapse because the eventual outcome is variable.