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Biomedical subjects

F Akasu

Publications and source records attributed to F Akasu.

At least 19 recordsLinked to original sources
PubMed1992

Impaired generation of high-affinity interleukin-2 receptors in the autologous mixed lymphocyte reaction in rheumatoid arthritis.

We examined the expression of high-affinity interleukin (IL)-2 receptors (IL-2R) as well as Tac and HLA-DR antigens on peripheral blood (PB) T cells from 11 rheumatoid arthritis (RA) patients and 8 healthy controls induced in the autologous mixed lymphocyte reaction (AMLR). The proportion of HLA-DR- and Tac-bearing T cells and expression of these activation antigens were higher in patients relative to controls (P less than 0.01) in freshly isolated unstimulated PB mononuclear cells. AMLR stimulation of RA T cells failed to induce an increase in the proportion of HLA-DR and Tac-bearing T cells which was observed in health controls. After AMLR stimulation the number of high-affinity IL-2R were significantly lower in RA patients compared with controls (P less than 0.01). The number of high-affinity IL-2R on patient T cells correlated strongly with AMLR reactivity as measured by [3H]thymidine incorporation (r = 0.821, P = 0.002). The results suggest that the AMLR defect in RA may result from impaired generation of high-affinity IL-2R.

Adult↗
PubMed1991

Monoclonal IgGs from an autoimmune MRL/Mp-lpr/lpr mouse induce an interleukin-3-dependent myeloid cell line to produce tumor necrosis factor alpha and interleukin-6.

We previously reported that two IgG mAbs, 1D11 and 1G10, derived from an autoimmune MRL/Mp-lpr/lpr(MRL/l) mouse, induced IL-3 synthesis in the IL-3-dependent myeloid cell line, FDC-P2/185-4. In this study, we found that these mAbs induced TNF-alpha and IL-6 production in FDC-P2/185-4 cells. Both TNF-alpha and IL-6 were secreted rapidly within 1 hr after the addition of mAb to the cells. Increases of TNF-alpha and IL-6 mRNA were also observed in FDC-P2/185-4 cells stimulated with MRL/l-derived mAb. The anti-Fc gamma RII mAb 2.4G2 suppressed TNF-alpha and IL-6 production induced by these mAbs. Our results suggest that some IgGs of MRL/l mice may have the capacity to induce cytokine synthesis in Fc gamma R-bearing cells.

Animals↗
PubMed1991

Interleukin 2-activated killer cells do not mediate autologous thyrocyte lysis in autoimmune thyroid disease in vitro.

Because of interest in IL-2, and IL-2-activated killer cell-induced hypothyroidism in humans, we attempted to study an in vitro system that might prove to illuminate this disorder. We have thus studied interleukin 2 (IL-2--0, 12.5, 25, or 50 U/mL) activated killer cell-mediated autologous thyrocyte lysis, as well as cytotoxic activity in IL-2-stimulated mononuclear cell supernatants in 7 patients with autoimmune thyroid disease (2 Graves' disease and 5 Hashimoto's thyroiditis) using the 51Cr release assay. Controls included 14 patients with nonautoimmune thyroid disease (3 nontoxic goiter, 8 follicular thyroid adenoma, 2 papillary thyroid carcinoma, and 1 medullary carcinoma of the thyroid). Soluble IL-2 receptor (sIL-2R) in supernatants of peripheral mononuclear cells stimulated by IL-2 from these patients also was measured. Whereas in the control preparations, IL-2-activated killer cell activity was increased in a dose-dependent fashion relative to the IL-2 concentration, as well as to the effector cell/target cell ratio, in preparations from patients with autoimmune thyroid disease, this activity was not elevated as the IL-2 concentration was increased. The susceptibility of thyrocytes to the lytic effect of IL-2-activated killer cells was higher in controls than that in autoimmune thyroid disease (at concentrations of IL-2 of 0, 12.5, 25, and 50 U/mL) (p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Studies of CD4+ (helper/inducer) T lymphocytes in autoimmune thyroid disease: demonstration of specific induction in response to thyroid peroxidase (TPO) in vitro and its relationship with thyroid status in vivo.

We have studied by flow cytometric analysis the antigen specific activation of CD4+ (helper/inducer) T lymphocytes by purified human thyroid peroxidase (TPO). Peripheral blood mononuclear cells were obtained from 26 patients with Graves' disease (GD), 16 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), and 14 normal subjects (N). Cells were cultured for 7 days in the presence or absence of TPO at final concentrations of 3, 30, and 300 ng/mL. When harvested, cells were reacted with an FITC-conjugated anti-CD4 and a PE-conjugated anti-HLA-DR murine monoclonal antibodies. The percentage of HLA-DR+ CD4+ cells (activated CD4+ cells) was determined by a flow cytometer. In the absence of TPO, CD4+ cells had been activated without any specific stimulant. This is known as the autologous mixed lymphocyte reaction (AMLR). In the AMLR, CD4+ cells from GD and HT were less activated compared to those from NG and N. Results of TPO-specific activation were expressed as an incremental increase of activated CD4+ cells (II) (percentage of activated CD4+ cells cultured with TPO minus percentage of activated CD4+ cells cultured without TPO). II of N, GD, HT, and NG were 0.37 +/- 0.21, 2.20 +/- 0.45,** 2.0 +/- 0.66,* and 0.35 +/- 0.27 (mean +/- SEM), respectively (**p less than 0.01; *p less than 0.05 vs N). When patients were further subdivided, the highest mean II was found in patients with hyperthyroid GD (p less than 0.01), followed by euthyroid HT (p less than 0.05) and euthyroid GD (p less than 0.05), however there was no significant difference between hypothyroid HT and N. In conclusion (1) AMLR reactivity of CD4+ cells from GD and HT was impaired, (2) however, CD4+ cells from both GD and HT were significantly more induced by TPO compared to N, and (3) this induction depends, in part, on the in vivo thyroid status.

Adolescent↗
PubMed1991

Effects of recombinant human interleukin-2 and tumor necrosis factor-alpha with or without interferon-gamma on human thyroid tissues from patients with Graves' disease and from normal subjects xenografted into nude mice.

We have compared the effects of interleukin-2 (IL-2) or tumor necrosis factor-alpha (TNF alpha) administration with or without interferon-gamma (IFN gamma) on Graves' and normal thyroid tissue xenografts in the nude mouse (in the absence of an intact immune system) in terms of possible functional, immunological, or histological changes. The dosages of recombinant human IL-2, TNF alpha, and IFN gamma given to each mouse were 250, 800, and 4000 U, respectively; they were injected ip daily for 6 consecutive weeks. The parameters measured included the free T4 index, thyroid autoantibodies, and mouse TSH during the course of the study. Thyroid epithelial cell (TEC) HLA-DR expression was measured in thyroid tissue before xenotransplantation and at death; in addition, light microscopic studies were carried out at those times. There were no significant differences in thyroid function between the results in unstimulated (control) animals and those obtained with cytokine administration in either group of tissues, with the exception of the group receiving TNF alpha together with IFN gamma; in this latter group, the free T4 index declined significantly 4-6 weeks after commencement of treatment in the animals with normal thyroid tissue xenografts. The reduction of thyroid function induced by the combination of IFN gamma and TNF alpha observed in normal thyroid tissue may be due to inhibition of thyroperoxidase and thyroglobulin gene transcription. However, there was no such effect on the Graves' thyroid tissue xenografts, perhaps because of down-regulation of this tissue in response to cytokines, after having been released from long term in vivo immune stimulation. On the other hand, TNF alpha plus IFN gamma induced TEC HLA-DR expression on both types of thyroid xenografts at death, although IL-2 alone did not induce HLA-DR expression, and IFN gamma induced TEC significantly only on normal thyroid xenografts (but not on Graves' xenografts). In light microscopic examination, Graves' thyroid xenografts treated with IL-2 alone or TNF alpha plus IFN gamma appeared normal at death. In addition, normal thyroid xenografts treated with the same cytokines did not show discernible differences compared to those at human surgery or when the xenografts were untreated at death. We conclude that Graves' TEC did not differ from normal TEC in any significant fashion at the time of death, aside from a reduced responsiveness to the stimuli applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The effect of xenotransplantation of human thyroid tissue following radioactive iodine-induced thyroid ablation on thyroid function in the nude mouse.

We have attempted to determine whether xenotransplanted human thyroid tissue into nude mice would act as a physiological substitute for the mouse thyroid gland after the mice had been rendered hypothyroid, using radioactive iodine (131I). The dosage of 0.2 millicuries of 131I was given to each mouse. The xenotransplantations of human thyroid tissue, i.e., normal, Graves' and nontoxic multinodular goitre, were carried out three weeks after radioactive ablation. The values of TSH in all mice rose to high levels (71 +/- 15.6 ng/ml, +/- SD) by three weeks after 131I administration. The TSH values in the mice declined rapidly and reached normal levels by 3-5 weeks after xenotransplantation. In addition, the serum T4 values were generally in the euthyroid range by 3-6 weeks after xenotransplantation. There were no marked differences in the changes of serum T4 and TSH when the three groups were compared. These results indicated that the xenografted human thyroid tissue permitted a return to a normal feedback system as reflected by normal serum TSH and T4 values in the animals. The Graves' thyroid tissue reverted to normal physiological function when removed from its human (abnormal) immune environment, signifying that Graves' thyrocytes are mere passive captives to immune events. This model should prove to be useful in the study of human thyroid physiology and pathophysiology.

Animals↗
PubMed1990

Serum IgG from an autoimmune prone mouse C3H/HeJ-gld/gld supports the interleukin-3-dependent cell line through an autocrine mechanism.

C3H/HeJ-gld/gld(C3H/gld) mice have been shown to develop massive lymphadenopathy with autoimmunity. In this study, we tested whether C3H/gld-IgG supports the growth of the IL-3-dependent cell line, FDC-P2/185-4. Serum IgG from C3H/gld mice stimulated FDC-P2/185-4 cells to proliferate. On the other hand, IgG from C3H/HeJ-+/+ did not show such activity. This activity increased with age in both sexes of C3H/gld mice. It was suggested that a monomeric IgG component was responsible for the proliferative activity of C3H/gld mouse sera. The cell-induced growth required Fc gamma receptors on FDC-P2/185-4 cells. FDC-P2/185-4 cells stimulated with C3H/gld-IgG, secreted IL-3, and grew by themselves, indicating an autocrine mechanism. Thus, cytokines produced by serum IgG may play an important role in the development of disease in mice bearing the autosomal recessive mutation gld.

Age Factors↗
PubMed1990

Polyclonal and monoclonal IgGs from MRL/Mp-lpr/lpr mice induce an interleukin-3-dependent cell line to produce interleukin-3 through an Fc gamma-receptor-mediated mechanism.

Serum IgG from autoimmune MRL/MP-lpr/lpr(MRL/l) mice induced IL-3 mRNA, IL-3 synthesis, and cell proliferation in the IL-3-dependent cell line, FDC-P2/185-4. Cell growth, induced by MRL/l-IgG, was suppressed by anti-IL-3 antibody, suggesting an autocrine mechanism. We established hybridomas from the splenocytes of a nonimmunized MRL/l mouse. The mAbs, produced by these hybridomas, also stimulated IL-3 synthesis and cell growth in FDC-P2/185-4 cells. Both anti-IgG-Fc antibody and anti-Fc gamma RII mAb, 2.4G2 suppressed the cell growth induced by these mAbs. Our results suggest that some IgGs of MRL/l mice may induce IL-3 synthesis in cells by binding to Fc receptors.

Animals↗
PubMed1990

In vitro production of interferon-gamma by peripheral blood from patients with Graves' disease, Hashimoto's thyroiditis and rheumatoid arthritis.

The production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells (PBMC), CD4 cells, or CD8 cells in response to interleukin-2 (IL-2) stimulation has been studied; the samples were obtained from 12 healthy control subjects, 19 patients with Graves' disease (10 hyperthyroid and nine euthyroid), 13 patients with Hashimoto's thyroiditis (four hypothyroid and nine euthyroid), and 15 patients with rheumatoid arthritis (11 active and four inactive). A dose of IL-2 (25 U/ml) was utilized to induce IFN-gamma by PBMC from all four groups. The incremental increase in IFN-gamma values (with IL-2 stimulation minus without stimulation) was significantly less in PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis than that in PBMC from control subjects. The values from PBMC in patients with Graves' disease in a euthyroid state were below normal but greater than those from patients with Graves' disease in a hyperthyroid state. The incremental increase in IFN-gamma values from Graves' disease PBMC correlated with the serum TSH values (r = 0.622, P less than 0.01), but not with thyroid autoantibodies (anti-thyroid microsomal antibodies, anti-thyroid microsomal antibodies, nor TSH-binding inhibitory immunoglobulin activities). The incremental increase in IFN-gamma from PBMC from both control subjects and Graves' disease was correlated with that from CD4 cells (r = 0.711, P less than 0.01), but not with that from CD8 cells. The production of IFN-gamma in response to IL-2 from PBMC in Graves' disease correlated inversely with thyroid function, appearing to reflect the very effect of hyperthyroidism in this process. The precise explanation of these phenomena remains unclear. The decreased response of IFN-gamma to IL-2 stimulation by PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis seems to be a non-specific phenomenon occurring in both organ specific autoimmune disease and systemic autoimmune disease. It may be due to a down-regulation in autoimmune disease of CD4 cells in response to IL-2, a decreased level of IL-2 cellular receptors or a decreased receptor affinity, associated increased soluble IL-2 receptors, or a defect of the intra-CD4 cellular IL-2 signal to produce or release IFN-gamma in the conditions studied.

Adult↗
PubMed1990

Peripheral blood T lymphocyte sensitization to thyroid microsomal antigen from patients with Graves' disease negative for circulating anti-thyroid microsomal antibodies.

We have studied thyrocyte HLA-DR expression induced by supernatants of peripheral blood mononuclear cells (PBMC) stimulated by thyroid microsomal antigen (TMA), as an index of sensitization of the T lymphocyte in autoimmune thyroid diseases; we have studied PBMC from 11 normal control persons and 19 patients with Graves' disease (GD) in whom serum anti-thyroid microsomal antibodies (AMA) were either not detectable (9 patients) or were positive (10 patients). Thyrocyte HLA-DR induction in response to TMA-treated PBMC supernatants from GD was significantly different from that of normal controls (p less than 0.05, ANOVA). TMA-stimulated GD PBMC supernatants increased thyrocyte HLA-DR index [TMA 1 ng/ml, SI 143 +/- 82 (mean +/- SD), p less than 0.05], but normal PBMC supernatants did not. However there was no significant difference in response in terms of the thyrocyte HLA-DR expression induced by TMA-stimulated PBMC supernatants between AMA seronegative vs seropositive GD. These results suggest the possibility of some dissociation of the activities of T lymphocytes and B lymphocytes in patients with GD in response to thyroid microsomal antigen with or without anti-thyroid microsomal antibodies.

Adult↗
PubMed1990

Serum interferon gamma levels in autoimmune thyroid disease.

The lymphokine, interferon gamma (IFN gamma) is considered to play an important role in the development of autoimmune thyroid disease (AITD); the main source of IFN gamma has been shown to be CD4 cells when stimulated by soluble antigen. We have measured the serum IFN gamma concentration in 42 patients with AITD (24 Graves' disease and 18 Hashimoto's thyroiditis) and 9 normal control subjects, using a sandwich enzyme-linked immunosorbent assay (ELISA) (detectable limit, 1 IU/ml). One of normal controls, 14 of the 24 patients with Graves' disease, and 5 of the 18 patients with Hashimoto's thyroiditis had detectable IFN gamma levels. Patients with Graves' disease were found to have higher concentrations of serum IFN gamma (11.6 +/- 15.8 IU/ml, mean +/- SD) than normal controls (1.1 +/- 0.3 IU/ml). However, the values in patients with Hashimoto's thyroiditis (9.4 +/- 15.5 IU/ml) were not significant when compared to those in normal controls. Serum IFN gamma values in patients with AITD did not correlate with serum anti thyroid autoantibodies (antithyroglobulin, antithyroid microsomal antibody, or TSH binding inhibitory immunoglobulin activity) or with thyroid function. Thus, increased in vivo production of IFN gamma in Graves' disease as evidenced in these serum concentrations might reflect T cell activity, but does not appear to be an accurate reflection of intrathyroidal events.

Autoantibodies↗
PubMed1989

Localized myxedema on the nasal dorsum in a patient with Graves' disease: report of a case.

We report the case of a 56-year-old Japanese female with Graves' disease associated with localized myxedema on the nasal dorsum. The patient developed localized myxedema concomitantly with hyperthyroidism before antithyroid therapy was given. The lesion was totally removed surgically, as it was small and well circumscribed. Although unusual locations of localized myxedema have been reported elsewhere, there is to date no case of localized myxedema on the nasal dorsum without involvement of the pretibial area reported in the literature. We discuss this unique feature of our patient.

Autoantibodies↗
PubMed1987

Demonstration of calcium-dependent proteases (calpains) and thyroglobulin proteolysis in hog thyroid cytosol.

Ca2+-dependent neutral proteases in hog thyroid cytosol were found to digest thyroglobulin. The protease activity was divided into two peaks by DEAE-cellulose column chromatography. Peak I was eluted at 0.2 M NaCl and required only a micromolar range of Ca2+ for its 50% activation, while peak II, which was eluted at about 0.4 M NaCl, displayed little activity until the Ca2+ concentration was increased at more than 10(-4) M. Among various inhibitors used, thiol protease inhibitors (leupeptin, E-64 and monoiodoacetic acid) were the most effective, whereas a calmodulin antagonist (trifluoperazine) and serine protease inhibitors (phenylmethyl-sulfony-fluoride and pepstatin A) were not effective, indicating that these Ca2+-dependent proteases corresponded to calpains 1 and 2. Among the substrates tested, casein was the best and thyroglobulin was also a good for calpain 2. By using immunoblotting procedure with anti-thyroglobulin antibody, it has been found that calpain 2 degrades thyroglobulin to yield 67 K and 46 K thyroglobulin and further that it also degrades 40 K thyroglobulin.

Animals↗
PubMed1986

Iodide-induced hypothyroidism in a patient with anorexia nervosa.

A 39-year-old woman who had been suffering from anorexia nervosa was found to have hypothyroidism. Serum T4, free T4, T3, free T3 and TSH were 3.19 micrograms/dl, 0.5 ng/dl, 15.3 ng/dl, 1.2 pg/ml and 162.1 microU/ml, respectively. On careful questioning, she was found to have taken an iodine-rich diet. The serum iodine concentration was 122 micrograms/dl (normal: 4-9 micrograms/dl) and urinary iodide excretion was 13.05 mg/day (normal: less than 2 mg). After withdrawal of the iodine-rich diet, her serum T4 gradually increased and TSH returned to the normal range. She was diagnosed as having iodide-induced hypothyroidism. However, no significant elevation of serum T3 or free T3 was observed. Serum T4, free T4, T3, free T3 and TSH were 7.85 micrograms/dl, 0.8 ng/dl, 13.6 ng/dl, 4.3 pg/ml and 6.02 microU/ml, respectively. The iodide-perchlorate discharge test result was negative. These findings suggest that there exists some unknown mechanism by which a patient with anorexia nervosa may be sensitive to excess iodide. Furthermore, it is of interest to note that in a recovery phase from the hypothyroid state, normalization of serum T4 rather than T3 is well-correlated to TSH secretion.

Adult↗
PubMed1978

The biphasic stimulatory and inhibitory effects of concanavalin A on thyroid activation induced by thyrotropin.

Concanavalin A (Con A) was tested for its ability to affect thyroid activation induced by TSH in mouse thyroid lobes. Pretreatment of thyroid lobes with Con A at concentrations from 1.55--400 microgram/ml was found to have biphasic stimulatory and inhibitory effects of the TSH-induced accumulation of cAMP and formation of colloid droplets. Low concentrations of Con A potentiated TSH activation of thyroidal formation of cAMP and endocytosis. In contrast, higher concentrations of Con A markedly inhibited these TSH effects. The inhibitory effects observed after preincubation with Con A were abolished by the addition of alpha-methyl-D-glucoside to the incubation medium. A high concentration of Con A also inhibited cAMP formation induced either by prostaglandin E2 or the long-acting thyroid stimulator. However, the basal and TSH-stimulated glucose oxidation in mouse thyroid lobes was not depressed by a high concentration of Con A. Uptake of 125 I-labeled Con A by thyroid tissues increased with time up to 1 h and was directly proportional to tissue weight. These findings suggest that the specific interaction between Con A and its receptors may lead to conformational changes in the structure of the membranes of the thyroid follicular cells which facilitate TSH-induced thyroid hormone secretion via the adenylate cyclase-cAMP system.

Animals↗
PubMed1978

Evidence for activation by beta2-adrenergic receptors of adenosine 3',5'-monophosphate formation in Ehrlich ascites tumor cells.

The existence of aminergic receptors in mouse Ehrlich ascites tumor cells was studied. L-Isoproterenol in vitro stimulated the formation of cAMP in isolated Ehrlich ascites tumor cells. Stimulation by isoproterenol of cAMP formation was not significantly inhibited by practolol, a beta1-adrenoceptor antagonist-Salbutamol, a beta2-adrenoceptor agonist, markedly stimulated the formation of cAMP in Ehrlich ascites tumor cells at concentrations from 10(-8)-10(-3) M. After the addition of salbutamol, cAMP levels reached a maximum in 10 min and declined to about 2-fold of the basal level to 30 min. The stimulation by salbutamol of cAMP formation was markedly inhibited by butoxamine, a beta2-adrenoceptor antagonist, but not by practolol. Furthermore, the effect of a maximal dose of salbutamol was additive to that of prostaglandin E2. Histamine and 4-methylhistamine, a histamine H2 receptor agonist, had no significant effects. Therefore, it is suggested that a beta2-adrenergic receptor exists in the membranes of Ehrlich ascites tumor cells in terms of the adenylate cyclase-cAMP system.

Albuterol↗