Biomedical subjects

T F Davies

Publications and source records attributed to T F Davies.

At least 19 recordsLinked to original sources

PubMed1992

Cloning and sequencing of a 1.3 KB variant of human thyrotropin receptor mRNA lacking the transmembrane domain.

We amplified human thyroidal cDNA using oligonucleotide primers designed to reveal putative human thyrotropin receptor (hTSHR) mRNA variants encoding the extracellular, ligand-binding domain but lacking the transmembrane domain. Whereas the major 4.3 kb hTSHR mRNA species was not amplified to detectable levels, several shorter products were detected. A strongly amplified 1 kb product was cloned and sequenced. It contained coding sequences at the 5' end which were colinear with exons 1-8 of the hTSHR gene, encoding most of the extracellular domain. This was followed at the 3' end by additional coding and noncoding information not present in the 4.3 kb transcript. A probe specific for the 5' end recognized polyadenylated thyroidal transcripts of 4.3, 1.7, and 1.3 kb, indicating the presence of several hTSHR mRNA variants. A probe specific for the 3' end recognized only the 1.3 kb transcript. The level of the 1.3 kb variant (hTSHR-v 1.3 mRNA) was about half that of the 4.3 kb hTSHR mRNA and twice that of the 1.7 kb variant. The presence of a thyroidal mRNA encoding both the signal peptide and ligand-binding region of the hTSHR, but not the seven transmembrane helices, provides the potential to produce soluble receptors which could play important roles in thyroid physiology and/or autoimmune thyroid disease.

Amino Acid Sequence↗

PubMed1992

T cells and human autoimmune thyroid disease: emerging data show lack of need to invoke suppressor T cell problems.

Human T cells recognize self and foreign antigens when such antigens are processed into small peptides and bound to molecules coded for by genes of the HLA region on chromosome 6. The part of the T-cell surface which is responsible for such recognition is a set of molecules coded for by a variety of genes and known as the T-cell-receptor complex. In animal models, T cells are able to transfer autoimmune thyroiditis and T cells have, therefore, long been implicated in the etiology of human autoimmune thyroid disease (AITD). Information gained from the study of intrathyroidal T cells and thyroid antigen-specific T-cell clones has shown that in patients with Graves' disease, mainly helper T-cell clones have been obtained, whereas in autoimmune (Hashimoto's) thyroiditis cytolytic T-cell clones may be predominant. Such thyroid antigen-specific T cells have now been shown to recognize one or other of the three major thyroid-specific antigens; thyroglobulin, thyroid peroxidase, or the TSH receptor and efforts are currently in progress to characterize the T-cell epitopes of these major thyroid autoantigens. Recent findings of restricted T-cell receptor V gene use amongst intrathyroidal T cells confirm the primary role of T cells in human thyroid autoimmune processes leading to AITD. However, the mechanisms whereby such autoreactive T cells escape deletion and anergy, and how they become activated, remain uncertain. There is compelling evidence that the thyroid cell itself, by expressing HLA molecules, and presenting antigen directly to the T cells, may initiate disease, perhaps after an external insult.

Amino Acid Sequence↗

PubMed1992

Characteristics of long-term human thyroid peroxidase autoantibody secretion in scid mice transplanted with lymphocytes from patients with autoimmune thyroiditis.

We have explored scid mice as an in vivo model to study lymphocyte function and autoantibody production in patients with autoimmune thyroiditis and thyroid peroxidase (hTPO) autoantibodies. Patient's peripheral blood mononuclear cells (PBMC) were transplanted into scid mice via intraperitoneal injections and human immunoglobulin G (hIgG) and thyroid autoantibody levels in the murine sera were monitored for a minimum of 3 months after transplantation. Human IgG reached maximum serum levels of > 3,000 micrograms/ml (mean +/- SEM = 1,199 +/- 354 micrograms/ml) after an average of 6.5 weeks. In reconstituted mice (hereafter named At-Scid-hu) substantial titers of anti-hTPO of up to 0.51 (ELISA index, normal range < 0.02) were observed over a period of 1-2 months, followed by a gradual decline. Immunization of AT-Scid-hu mice with immunogenic, recombinant human hTPO (rec-hTPO) failed to enhance hTPO-Ab levels. Furthermore, there was no correlation between the magnitude of human IgG in the murine serum and concomitant levels of anti-hTPO. Murine thyroid function was unaffected by the transplantation of PBMC, as evidenced by normal serum thyroxine (T4) levels, and lack of specific pathologic changes in the thyroid. These data indicate, for the first time, the potential for longer-term human thyroid autoantibody secretion in the scid mouse reconstitution model allowing for further investigation of the regulatory factors inpinging on the human B cells surviving in the murine environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Evidence for selective accumulation of intrathyroidal T lymphocytes in human autoimmune thyroid disease based on T cell receptor V gene usage.

We have investigated the T cell receptor V alpha and V beta gene family usage by T lymphocytes infiltrating affected thyroids in patients with autoimmune thyroid disease. We show that the intrathyroidal T lymphocytes from patients (n = 6) with autoimmune thyroid disease display a widespread usage of V beta gene families with an average of 14.4/19 V beta gene families similar to the peripheral T lymphocytes of the same patients. Because we recently reported that the utilization of V alpha gene families is markedly reduced within these mitogen-stimulated intrathyroidal T cell populations, as well as within intact tissue from similar patients (n = 4) (overall mean of 4.0/18 families detected), these results indicate that in thyroids of patients with autoimmune thyroid disease the lymphocytes are selectively accumulating based on their V alpha rather than V beta elements. This preferential hTcR V alpha and widespread V beta gene usage was not mimicked in most 7-d autologous mixed lymphocyte reactions using non-T cell stimulators (n = 6) or EB-virus immortalized autologous B cell lines (n = 3). Hence, the selective V gene utilization by intrathyroidal T cells is likely to be secondary to multiepitopic thyroidal autoantigens activating thyroid infiltrating T cells or to the presence of a superantigenlike thyroidal self-antigen, capable of determining a selective infiltration or activation of a variety of T lymphocytes on the basis of their V alpha gene usage.

Autoantibodies↗

PubMed1992

The positive regulation of human thyrotropin (TSH) receptor messenger ribonucleic acid by recombinant human TSH is at the intranuclear level.

We have assessed the regulatory influence of human recombinant TSH (rec-hTSH) on its homologous receptor (TSHR) using a well characterized human fetal thyroid monolayer cell culture technique. Under the culture conditions employed, fetal human thyroid cells showed basal expression of TSHR-specific mRNA transcripts, and the addition of rec-hTSH (1 U/L) induced up to an 8-fold increase in specific mRNA over a 48-h observation period. This induction was simulated by bromo-cAMP in a dose-dependent manner, indicating that the stimulatory effect of rec-hTSH was active at the postreceptor level. Furthermore, there was no detectable increase in the transcription rate of the TSHR gene after stimulation with rec-hTSH for 12-36 h, although a marked increase in thyroglobulin-specific mRNA was observed. Rec-hTSH also had no influence on the half-life of TSHR-specific mRNA, which remained at approximately 16 h in the presence or absence of rec-hTSH. These data indicate that rec-hTSH induced up-regulation in human thyroid cell TSHR-specific mRNA and that the mechanism of this regulation was likely to be secondary to a posttranscriptional nuclear event involving changes in the regulation of primary unspliced mRNA for the TSHR.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Genetics of autoimmune thyroid disease: lack of evidence for linkage to HLA within families.

Clinical and epidemiologic observations, including the association of Graves' disease (GD) and Hashimoto's thyroiditis (HT) with the HLA gene complex, support a role for specific disease-related genes in the development of autoimmune thyroid disease (AITD). The combination of HLA and immunoglobulin heavy chain allotypes (Gm) has previously been reported to be predictive of AITD in multiply affected Japanese families. We have investigated the immunogenetics of AITD in families in the United States. Twenty-seven pedigrees including 15 with GD, 8 with HT, and 4 with both HT and GD were immunogenetically typed and analyzed for population and within family disease associations. The majority of families (63%) were multiplex for AITD. HLA-DR3 was increased in affected family members with GD and HLA-DR5 was increased in affected family members with HT. Formal linkage analysis was applied to test for coinheritance of disease with the HLA locus within families. The LIPED computer program was used to calculate the probability of linkage in terms of the lod score. Evidence from linkage analysis was consistently against linkage of either GD or HT to the HLA region under various penetrances and different modes of inheritance. The combination of HLA and Gm was not found to be predictive of disease in 7 selected multiplex families with multigenerational instances of AITD. T cell function was also examined in 3 pairs of siblings genetically identical for HLA and Gm but discordant for disease expression. We found no evidence of a global T cell defect in the small number of patients examined. We conclude that whereas there is an association of AITD with the HLA region, our linkage analysis demonstrates that alleles of the HLA region are not cosegregating with either GD or HT within these families. Thus, whereas HLA may increase susceptibility to AITD, as shown by the existence of an HLA association, the major genetic influence on the inheritance of AITD must be at another locus.

B-Lymphocytes↗

PubMed1992

A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction.

Immune function in normal pregnancy and the postpartum period remains poorly defined. We hypothesized that a comparative study between pregnant women with normal and abnormal immune function would further our understanding of the immune mechanisms of pregnancy. We chose to study a cohort of pregnant women at risk for the development of postpartum thyroid dysfunction (PPTD) as well as a group of normal controls. We chose PPTD as the model for abnormal immune function because of the relative ease of monitoring disease development and the relatively high prevalence for PPTD reported in earlier studies. Five hundred and fifty-two women were screened for the presence of thyroid autoantibodies in the first trimester of pregnancy. Thirty-three thyroid autoantibody-positive women and 28 thyroid autoantibody-negative women were followed prospectively throughout pregnancy and 6 months into the postpartum period. Lymphocyte subset analyses, thyroid function tests, and thyroid autoantibodies (antihuman thyroglobulin and antithyroid peroxidase) were performed at defined intervals. All patients were HLA serotyped. Normal pregnancy was principally characterized by decreased CD4+ T-cells and increasing CD8+ T-cells, causing a significant fall in the CD4+/CD8+ ratio in late pregnancy and into the postpartum period. Women who developed PPTD had 1) a higher CD4+/CD8+ ratio (P = 0.04), 2) activation of T-cells in the postpartum period (P = 0.02), and 3) significantly higher thyroid autoantibody titers (antihuman thyroglobulin, P = 0.02; antithyroid peroxidase, P = 0.0018). We found an overall incidence for PPTD of 8.8%. These data demonstrated that women who were thyroid autoantibody positive in the first trimester of pregnancy had a one in three chance of developing PPTD. We observed a significant fall in the T-cell helper/suppressor ratio in normal pregnant women, which was associated with distinct T-cell subset changes. This pregnancy-initiated T-cell regulation reflected an overall suppression of immune function. The development of PPTD was a frequent postpartum event in our population and was associated with a triad of immune markers: a reduction in the normal immune suppression of pregnancy (as indicated by higher T-cell helper/suppressor ratios), enhanced postpartum T-cell activation, and elevated thyroid autoantibodies. The reduction in the degree of immune suppression was, therefore, a major factor in the development of PPTD. Our results define immunological changes that occur in normal pregnancy and distinct immunological abnormalities necessary for the development of PPTD.

Autoantibodies↗

PubMed1992

Human chorionic gonadotropin (hCG) interacts directly with recombinant human TSH receptors.

We have previously shown that highly purified urinary hCG has the potential to both stimulate the intracellular accumulation of cyclic AMP and induce growth of immortalized rat thyroid cells. We have now compared the ability of recombinant human TSH and purified urinary hCG preparations to stimulate Chinese hamster ovary (CHO) cells which have been transfected with the human TSH receptor. Only transfected CHO cells expressing recombinant TSH receptors, but not control CHO cells, were stimulated by hCG to release cyclic AMP in a dose-related manner and the effect of 100 IU of HCG was equivalent to approximately 9.2 uU of rec-hTSH. These data demonstrate that hCG interacts directly with the human TSH receptor.

Animals↗

PubMed1992

Preferential use of T-cell receptor V genes in human autoimmune thyroid disease.

We review here our analyses of hTcR V gene activity within the thyroid glands of patients with autoimmune thyroid disease. Our data, based on thyroid aspiration specimens, indicate that early in the onset of Graves' disease there is a marked restriction in both hTcR V alpha and V beta gene families utilized by intrathyroidal T-cells. Later, however, and as seen in surgical thyroid specimens from patients with long term disease, there appears to be a loss of V beta restriction for unclear reasons. In contrast, patients with Hashimoto's thyroiditis are usually diagnosed later in the natural history of the disease and appear to show much less hTcR V gene family restriction. The mechanisms driving the use of few and many hTcR V genes within the thyroid gland are likely to be complex and may reveal important insights into disease pathogenesis.

Autoimmune Diseases↗

PubMed1992

Graves' disease and its retroorbital aspects.

Graves' disease is a common, familial, but easily treated condition caused by unique autoantibodies which act as TSH agonists. Patients with the diagnostic eye signs of Graves' disease, however, require more careful treatment than those patients with principally thyroidal involvement because destructive therapy to the thyroid gland may exacerbate the eye disease. The cause of ophthalmic eye disease appears to be "crossover specificity" by the immune system for a recurrent antigen in extraocular muscles, fibroblasts, and the thyroid gland. Treatment directed at the autoimmune response may offer the most appropriate therapy in the years to come.

Exophthalmos↗

PubMed1991

Evidence of limited variability of antigen receptors on intrathyroidal T cells in autoimmune thyroid disease.

BACKGROUND: Patients with autoimmune thyroid diseases, including Graves' disease and Hashimoto's disease, have marked lymphocytic infiltration in their thyroid glands. We examined the gene for the variable regions of the alpha-chain of the human T-cell receptor (the V alpha gene) in intrathyroidal T cells to determine whether the infiltration is a secondary heterogeneous immune response or a more restricted, and therefore primary and presumably pathogenetic, reaction to thyroid autoantigens. METHODS: We used the polymerase chain reaction to detect small numbers of T cells expressing the variable region of the V alpha gene. Different oligonucleotides were used to amplify complementary DNA for the 18 known families of the V alpha gene in intrathyroidal T cells from 9 patients with autoimmune thyroid disease. We compared the findings with the results in patients with nonautoimmune thyroid disease as well as those in normal subjects. RESULTS: We found marked restriction in the expression of T-cell-receptor V alpha genes by T cells from the thyroid tissue of patients with autoimmune thyroid disease. An average of only 5 of the 18 V alpha genes were expressed in such samples, as compared with 17 V alpha genes expressed in peripheral-blood T cells from the same patients. No such restriction was found in thyroid tissue from patients with nonautoimmune thyroid disease. The predominantly expressed V alpha genes differed from patient to patient, however, with no clear association with the type of disease. CONCLUSIONS: Intrathyroidal T-cell accumulation in autoimmune thyroid disease is highly restricted and points to the primacy of T cells in causing thyroid disorders. These results present the possibility of using antibodies to the T-cell receptor for the specific inhibition of abnormal T-cell function in autoimmune thyroid disease.

Antigens, CD↗

PubMed1991

The SCID-hu mouse and thyroid autoimmunity: characterization of human thyroid autoantibody secretion.

Severe combined immunodeficient (SCID) mice were injected with peripheral blood mononuclear cells (PBMC) from normal individuals and 14 out of 18 had detectable serum human (h) IgG (maximum levels providing a mean +/- SEM 934 +/- 213 micrograms/ml) and IgM (253 +/- 93 micrograms/ml) at 3-6 weeks after transplantation. Serum human immunoglobulin levels were maximum 6-12 weeks after transplantation and declined to low levels over the subsequent 5 months. Human B cells constituted up to 10% and human T cells up to 40% of cells in the peripheral circulation and spleens of these animals 2-3 weeks after transplantation, PBMC, or intrathyroidal (IT) lymphocytes, from 6 patients with Graves' disease and high serum levels of thyroid autoantibodies were transplanted into 30 SCID mice (Graves' SCID-hu). Although serum human immunoglobulins were observed in only low amounts in the animals receiving IT lymphocytes (n = 4), increased levels of hIgG or hIgM were more easily detectable in 19 Graves' SCID-hu mice that received PBMC. The Graves' SCID-hu mice had significantly lower mean levels of hIgG and hIgM than those observed following transplantation of normal PBMC (mean maximum 328 +/- 113 and 32 +/- 21 micrograms/ml, respectively). Six of these 19 mice had detectable human autoantibody to thyroid peroxidase (TPO, as microsomal antigen) between 3 and 8 weeks after transplantation, with titers ranging from 0.05 to 0.39 (normal SCID-hu serum less than 0.02 ELISA Index). No abnormal thyroid hormone (T4 and T3) levels or thyroiditis was seen when compared to normal SCID-hu mice. Immunization of reconstituted SCID mice with recombinant immunoactive human TPO antigen failed to initiate anti-TPO in normal PBMC-treated mice nor did it increase the titer of human anti-TPO in the anti-TPO positive animals. In conclusion we successfully established human thyroid autoantibody secretion in the SCID-hu mouse and characterized the transient nature of the model. Further studies will be required to achieve successful antigen presentation in this system.

Animals↗

PubMed1991

Thyroid-specific T cells in the normal Wistar rat. I. Characterization of lymph node T cell reactivity to syngeneic thyroid cells and thyroglobulin.

Wistar rats are susceptible to the induction of experimental autoimmune thyroiditis (EAT) and recently a cloned Wistar thyroid epithelial cell line (WRT) has become available. In this study we have examined the in vitro proliferative response of Wistar rat lymphoid cells to the WRT cells as a model for better understanding thyroid cell-T cell interactions. Lymph node (LN) cells from normal Wistar rats showed an early and vigorous response to syngeneic thyroid cells (WRT). Further examination of the Wistar phenomenon revealed that unpurified lymphoid cells were also able to mount a proliferative response to rat thyroglobulin. The Wistar LN cell response to WRT cells consisted of T cell proliferation that was both MHC class I and class II restricted. There was a greater proliferation of CD8+ than CD4+ T cells, but WRT-stimulated lymphoblast cells were not cytotoxic to 51Cr-labeled WRT cell targets. These data suggest that normal Wistar rats have circulating thyroid-specific T cells that may be related to their known susceptibility to EAT. Furthermore, the interaction between such thyroid-specific T cells and cloned syngeneic thyroid cells offers a unique model for the further investigation of thyroid-immune interactions and the escape from tolerance induction.

Animals↗

PubMed1991

Thyroid-specific T cells in the normal Wistar rat. II. T cell clones interact with cloned wistar rat thyroid cells and provide direct evidence for autoantigen presentation by thyroid epithelial cells.

Strains of rat differ in their susceptibility to experimental autoimmune thyroiditis (EAT). We recently observed that the normal Wistar rat has lymph node (LN) T cells which recognize the newly available cloned Wistar thyroid cell line (WRT) and/or rat thyroglobulin (rTg). We have now cloned thyroid-specific T cells and characterized their interaction with the WRT target cell. Twenty-three T cell clones were tested for their reactivity to syngeneic thymocytes, WRT cells alone, or WRT cells with thymocytes. All the clones were of the CD4+CD8- phenotype. Seven of 23 T cell clones proliferated in the presence of WRT cells alone or with the combination of WRT cells and thymocytes, exhibiting stimulation indices of 1.5 to 5. In all but one of the T cell clones responding to WRT cells alone was there no evidence that the additional presence of thymocytes supplied a stronger "second" proliferative signal than the WRT cells. These WRT-reactive clones which were able to be more extensively characterized were MHC class II restricted, secreted rat interferon (IFN)-gamma in response to WRT cell exposure, and one clone showed cross-reactivity with rTg antigen. Induction of WRT cell MHC class II antigen by prior treatment with IFN-gamma failed to further enhance the WRT cell-induced T cell proliferation. These data provide the first evidence for direct antigen presentation by thyroid epithelial cells (TECs) in the absence of other antigen-presenting cells. Furthermore, they provide evidence that TECs are able to provide the appropriate "second" signals required for T cell activation and successful autoantigen presentation.

Animals↗

PubMed1991

Absence of lutropin (LH) receptor mRNA in the rat thyroid: further evidence for specificity cross-over at the thyroid-stimulating hormone receptor level.

Chorionic gonadotropin (CG) and purified lutropin (LH) activate intact thyroid tissue and isolated thyroid cells. A recent report has suggested that the presence of aberrant LH/CG receptors in human and rat thyroid tissue may interact with gonadotropin thus explaining the mechanisms of thyroid cell stimulation. To detect putative thyroidal LH receptor mRNA, a segment of the transmembrane region containing domains 3 through 6 of the rat (r) LH receptor was targeted for amplification using the polymerase chain reaction (PCR). cDNA prepared from a rLH receptor-positive control tissue (testis) was efficiently amplified under stringent annealing conditions giving a 486 bp product as predicted. However, cDNAs from thyroidal tissue and from the thyroid-stimulating hormone (TSH)- and hCG-responsive 1B-6 subclone of Fisher rat thyroid cells (FRTL-5) yielded no detectable 486 bp product. A smaller (non-LH) fragment amplified to similar extents from both testis and thyroidal cDNAs provided a useful internal control for amplification. This allowed the conclusion that specificity cross-over between LH/CG and TSH occurs at the TSH receptor and that the LH/CG receptor gene is transcriptionally silent in rat thyroidal cells.

Animals↗

PubMed1991

A 64 kDa membrane antigen is a recurrent epitope for natural autoantibodies in patients with Graves' thyroid and ophthalmic diseases.

OBJECTIVE: We have explored the recently described 64 kDa extraocular muscle antigen that is associated with autoantibodies in the serum of patients with severe Grave's ophthalmopathy. The localization of the antigen and the specificity of autoantibodies for both eye muscle antigens and ophthalmopathy patients were investigated. DESIGN: Western blotting and immunoprecipitation of metabolically labelled antigen from eye muscle and control tissues with sera from ophthalmopathy, Graves' without ophthalmopathy, and normals were used. PATIENTS: Sera from normals (n = 9), patients with recent onset Graves' ophthalmopathy (n = 23), and patients with Graves' disease without ophthalmopathy (n = 8) were utilized. MEASUREMENTS: Immunoblots using detergent phase separated (amphiphilic) antigen preparations from fetal eye muscle, skeletal muscle and control tissues were quantitated. Metabolically labelled eye muscle and skeletal muscle antigens were immunoprecipitated using patient and control IgG. RESULTS: In the eye muscle detergent phase, immunoreactivity around 64 kDa was detected in 30% of the patients with ophthalmopathy (n = 23) as well as 38% of patients with Graves' disease and no ophthalmopathy (n = 8) and in 30% of normal sera (n = 9). There was significantly more of this anti-64 kDa reactivity in sera from the ophthalmopathy patients compared with the normals (P less than 0.01). 64 kDa reactivity to detergent phase antigens prepared from human thyroid, skeletal muscle, brain, and liver was also observed with these positive sera indicating the polyreactivity of the IgG interactions to conserved antigens in this region. CONCLUSIONS: We conclude that IgG antibodies binding to a recurrent 64 kDa antigen are present in many normal human sera, with increased concentrations detectable in sera from Graves' ophthalmopathy patients. Such 'specificity-crossover' with similar molecular weight transmembrane antigens is likely to be caused by natural autoantibodies reacting with recurrent autoepitopes rather than a factor aetiological in the disease process.

Adult↗

PubMed1991

Thyrotropin receptor autoantibodies induce human thyroid cell growth and c-fos activation.

Graves' disease encompasses hyperthyroidism and a diffuse goiter associated with autoantibodies to the TSH receptor (TRAb). Although the cause of the goiter formation has been attributed to TRAb, the limited growth pattern of human adult thyroid cells in vitro has caused such a conclusion to be based on studies of nonhuman thyroid cell growth. We have recently characterized a predictable and precise technique for the measurement of human thyroid cell proliferation and function using fetal thyroid cells and have used this system to examine the influence of TRAb on human thyroid cell growth. Highly purified human immunoglobulin G (hIgG) preparations from normal individuals (n = 5) had no significant influence on human thyroid cell growth. However, hIgG from patients with detectable TRAb (TRAb-hIgG) (n = 13) induced a dose-related increase in extracellular cAMP (maximum effect at 0.1 mg/ml) and a 3-fold increase in human thyroid cell growth over a 4-day period (maximum effect at 1.5 mg/ml). Under basal thyroid cell culture conditions there were detectable, but low, levels of mRNA specific for the protooncogene c-fos, and this was markedly, and rapidly, induced by the addition of TRAb-hIgG but not normal hIgG. These data demonstrate induction of cellular growth by TRAb-hIgG in an homologous human thyroid cell culture system. Such observations support the hypothesis that goiter formation in patients with Graves' disease is, at least in part, secondary to the growth stimulating activity of TRAb-hIgG.

Adolescent↗

PubMed1991

Recombinant human thyroid-stimulating hormone: initial bioactivity assessment using human fetal thyroid cells.

We have assessed the bioactivity of newly available recombinant human TSH (rec-hTSH) using human fetal thyroid cells, with the longer term aim of assessing its use for clinical applications. Rec-hTSH caused a consistent and dose-related increase in thyroid monolayer cell cAMP release and human thyroglobulin (hTg) secretion, confirming its bioactivity. Repetitive studies (n = 5) allowed us to derive an estimated biopotency for the rec-hTSH preparation examined of 5.6 IU/mg compared to 10 IU/mg for commercially available bovine TSH for human use. The rec-hTSH had a bioimmune ratio of 0.55, similar to that of purified pituitary hTSH standards, Furthermore, rec-hTSH induced thyroid epithelial cell growth, as evidenced by a decrease in thyroid cell doubling time from 54 +/- 2.1 to 31 +/- 1.7 h (P less than 0.005). Hence, rec-hTSH is a potent glycoprotein hormone preparation when measured in a homologous human thyroid cell culture system. Rec-hTSH could serve as a future definitive International Standard and has the potential for a useful diagnostic and therapeutic reagent.

Cell Division↗