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Biomedical subjects

N Yoshikawa

Publications and source records attributed to N Yoshikawa.

At least 91 records · Page 5Linked to original sources
PubMed1998

Immunohistological study in sixteen children with acute tubulointerstitial nephritis.

Sixteen children (7 boys and 9 girls, aged 1.9 to 14.8 years) diagnosed with acute tubulointerstitial nephritis [ATIN: 4 drug-induced, 6 infection, 2 tubulointerstitial nephritis and uveitis syndrome (TINU), and 4 unclassified] were studied to characterize the nature of the interstitial mononuclear cells involved in each clinical picture of the disease Six children with asymptomatic microscopic hematuria whose histology was a minimal change in renal biopsy were studied as controls. The enzyme immunoassay was carried out using the biopsy specimen obtained from 4 to 42 days after the onset of illness. In ATIN, the number of renal interstitial infiltrating CD3, CD4, and CD8 T lymphocytes, respectively, was significant larger than that in the minimal change kidneys [CD3 T cells; median 94 (range 3.2-330)/mm2 interstitial area vs. median 7.8 (range 1.1-23), p = 0.003, CD4 T cells; 11 (range 0.5-78) vs. 1.5 (range 0-7.7), p = 0.018, CD8 T cells; 22 (range 1.0-150) vs. 2.9 (range 0-14), p = 0.047]. In addition, a positive correlation was found between the CD3 and CD4 T cells. On the other hand, in regard to the relationship between the CD3 and CD8 T cells, CD8/CD3 was extremely low in 3 cases in the infection-induced group, but the other 3 groups included no extremely low CD8/CD3 cases. Although interstitial monocytes/macrophages were smaller than the T lymphocytes in number, a positive correlation was revealed between the T lymphocytes and monocytes/macrophages (CD3 T cells vs. monocytes/macrophages; r = 0.53, p = 0.039). No relationship was found between the duration from the onset of illness to renal biopsy and mononuclear cell involvement. These findings suggest that cellular immunity, mainly T lymphocytes, may play a role in the pathogenesis of ATIN in children.

Acute Disease↗
PubMed1998

[Standard versus long-term prednisolone with sairei-to for initial therapy in childhood steroid-responsive nephrotic syndrome: a prospective controlled study].

The most appropriate initial treatment for children with steroid-responsive nephrotic syndrome is controversial. Initial treatment with 18-week prednisolone and the Chinese herbal medicine. Sairei-to, may prevent subsequent relapse. To determine whether similar results can be obtained with a combination of just initial 8-week prednisolone and Sairei-to, we compared the effects of such treatment with those of treatment with 18-week prednisolone and Sairei-to in 196 children with steroid-responsive nephrotic syndrome. The patients were randomly assigned to receive 8-week (group 1) or 18-week (group 2) prednisolone for the initial therapy. All patients received Sairei-to for 2 years in addition to prednisolone. Eighty-eight of the 98 patients in group 1 and 83 of the 98 patients in group 2 completed their trial. At entry, the two groups of patients did not differ in their clinical and laboratory findings. During the 2-year trial, 62 group 1 patients (70%) and 54 group 2 patients (65%) had relapses, and 19 group 1 patients (21%) and 20 group 2 patients (24%) had frequent relapses. The present study demonstrates that a combination of initial 8-week prednisolone and 2-year Sairei-to is effective in children with steroid-responsive nephrotic syndrome.

Anti-Inflammatory Agents↗
PubMed1997

Grapevine berry inner necrosis, a new trichovirus: comparative studies with several known trichoviruses.

Biological, morphological and serological properties of grapevine berry inner necrosis virus (GINV), the casual virus of grapevine berry inner necrosis disease occurring in Japan, were compared with those of several known trichoviruses. Host range and particle length of GINV were quite similar to those of apple chlorotic leaf spot trichovirus (ACLSV). In ultrathin sections of the infected tissues, GINV particles existed in aggregated masses in the cytoplasm of vascular parenchyma and mesophyll cells. No virus specific inclusion bodies, such as pinwheels, viroplasmas or vesicles were observed. Serological relationships were not found between GINV and ACLSV, grapevine virus A or grapevine virus B. The cDNAs of the 3'-terminal region of the GINV genome were synthesized from poly (A)+RNAs extracted from infected tissues by PCR-selected cDNA subtraction and 3'-RACE PCR. The sequence of the 3'-terminal 2469 nucleotides contained three open reading frames (ORF) encoding a protein with the conserved motifs of RNA polymerase (ORF1), a 39 kDa putative movement protein (ORF2) and a 22 kDa protein (ORF3). The 22 kDa protein expressed in Escherichia coli reacted with antiserum against GINV, indicating that it is the coat protein of GINV. Polymerase and coat protein amino acid sequence comparisons and phylogenetic analyses with nine species of the genera Trichovirus and Capillovirus indicated that GINV is a new trichovirus relatively close to ACLSV.

Amino Acid Sequence↗
PubMed1997

Shear-stress causes polarized change in cytoplasmic calcium concentration in human umbilical vein endothelial cells (HUVECs).

Using a newly developed, parallel-plate flow-chamber for confocal laser scanning microscopy (CLSM), we studied the distribution and temporal changes in intracellular Ca2+ concentration ([Ca2+]i) in individual HUVECs stimulated by shear-stress. In the presence of ATP, shear-stress (1-10 dyne/cm2) caused a rise in [Ca2+]i, whereas no such response was observed in the absence of ATP or in the presence of Ni2+, a nonspecific, plasma membrane Ca2+ channel blocker. These results suggest that both ATP and Ca2+ influx are essential for the increase in [Ca2+]i in response to shear stress at less than 10 dyne/cm2. Analysis of [Ca2+]i distribution revealed a repetitive intracellular 'Ca2+ wave' originating from the upstream edge of the cell in some populations of HUVECS, which was transmitted to the downstream of the cell. The polarized [Ca2+]i response induced by shear-stress might be integral to polarized cellular reactions such as remodeling of endothelial lining.

Adenosine Triphosphate↗
PubMed1997

Coexistence of an autonomously functioning thyroid nodule in a patient with Graves' disease: an unusual presentation of Marine-Lenhart syndrome.

A 44-year-old woman developed hyperthyroidism due to the coexistence of Graves' disease and an autonomously functioning thyroid nodule (AFTN). Anti-thyrotropin receptor antibody (TRAb) was strongly positive (83.2%), and a thyroid scan initially showed diffuse uptake of Tc-99m pertechnatate in both lobes and further increased uptake in accordance with the right lobe nodule. The nodule in the right lobe was histologically diagnosed as thyroid follicular adenoma. After she was maintained in a euthyroid state by treatment with Methymazole (MMI), thyroid uptake of Tc-99m in the nodule became lower and was slightly suppressed by T3 administrations probably due to its dependence on TSH. Subtotal thyroidectomy was performed and she subsequently became euthyroid with negative TBII activity. It is concluded that she had a coexisting functioning nodule with Graves' disease (Marine-Lenhart syndrome) and that the nodule changed from hot to cool along with the anti-thyroid treatment, unlike usual cases of this syndrome showing a cold nodule on the initial imaging under the hyperthyroid state. Repeated Tc-99m pertechnatate thyroid scans were helpful in evaluating the reaction of MMI and TSH in both lesions separately in the present case.

Adenoma↗
PubMed1997

Simultaneous xenotransplantation of human Graves' thyroid tissue and autologous bone marrow cells in severe combined immunodeficient mice: successful reconstitution of human Graves' hyperthyroidism.

Human thyroid xenografts and the autologous bone marrow (BM) cells from five patients with Graves' disease (GD) were simultaneously xenografted into severe combined immunodeficient (SCID) mice to study the role of BM cells for the perpetuation of human GD autoimmunity and hyperthyroidism. All SCID mice engrafted with thyroid tissue (TH) alone, TH + autologous peripheral blood mononuclear cells, and TH + autologous BM cells produced similar amounts of human IgG; however, the production in TH + BM-engrafted mice peaked later than that of mice without BM. Production of thyroperoxidase antibody and thyroglobulin antibody in TH + BM-bearing SCID mice peaked in later weeks after xenografting than in those without BM. Moreover, human Graves' hyperthyroidism was actually reconstituted in TH + BM-transplanted mice; this was confirmed by (A) significantly higher levels and longer periods of secreting thyroid-stimulating antibody than those in mice without BM engraftment. (B) persistent hyperthyroxinemia up to the end of the experiment. (C) extremely high radioidine uptake of the xenografted thyroid tissue, and (D) histological findings of the maintenance of hyperplastic change of the xenografted thyroid epithelial cells. Human BM stem cells (CD34) were identified only in mice with TH + BM xenografts when analyzed by immunohistochemistry. In conclusion, (A) we have developed an animal model for human hyperthyroid GD by simultaneous xenotransplantation of GD thyroid tissue plus autologous BM cells into SCID mice, and (B) BM cells have a crucial role for perpetuating human GD autoimmunity and hyperthyroidism in this system.

Adult↗
PubMed1997

CJ-12,954 and its congeners, new anti-Helicobacter pylori compounds produced by Phanerochaete velutina: fermentation, isolation, structural elucidation and biological activities.

Seven new phthalide compounds with anti-Helicobacter pylori activities were isolated from the basidiomycete Phanerochaete velutina CL6387. The two most potent phthalide compounds, CJ-12,954 and CJ-13,014, have MICs of 5 ng/ml. The structure-activity relationship shows that the presence of a spiroketal part in addition to the phthalide part, greatly enhances the activity. The phthalide compounds appear to be specific for H. pylori, since they did not show antibacterial activities when tested against a panel of other microorganisms.

Anti-Bacterial Agents↗
PubMed1997

Evaluation of rectal mucosal hemodynamics in patients with liver cirrhosis using reflectance spectrophotometry.

OBJECTIVES: Portal hypertensive colonopathy is observed in patients with liver cirrhosis. To determine the correlation between rectal mucosal hemodynamics and portal hypertensive colonopathy, we observed rectal mucosal findings and measured rectal mucosal hemodynamics in patients with liver cirrhosis. METHODS: Thirty-four patients with liver cirrhosis and 16 healthy control subjects were simultaneously examined for rectal mucosal findings by colonoscopy and indices of rectal mucosal Hb concentration (RHb) and rectal mucosal oxygen saturation by reflectance spectrophotometry. Endoscopic findings in the rectal mucosa of patients with liver cirrhosis included vascular ectasias, blue veins, and varices. We investigated the relationship between rectal mucosal hemodynamics and clinical parameters of liver cirrhosis (Child-Pugh classification, the amount of indocyanine green remaining in the blood 15 min after its injection, and ascites). Patients with hepatocellular carcinoma, colonic cancer, multiple colonic polyps, or severe anemia were excluded. RESULTS: Rectal mucosal lesions were observed in 11 patients with liver cirrhosis (32.4%). In the hemodynamic studies, we found significantly increased RHb values in the cirrhosis group as compared with the control group. On the other hand, there was no significant change in rectal mucosal oxygen saturation between the two groups. A significant increase in RHb was observed in patients with rectal mucosal lesions in the cirrhosis group. RHb in the cirrhosis group correlated with grade of Child-Pugh classification. Increased RHb decreased in parallel after portal decompression by creation of a transjugular intravenous portosystemic stent shunt. CONCLUSIONS: The rectal mucosal lesions in liver cirrhosis correlate with an increase in RHb, which correlates with portal hypertension.

Ascites↗
PubMed1997

[A clinicopathological study of 90 children with acute renal failure].

Clinical presentation, laboratory findings, renal biopsy findings and subsequent clinical course were studied retrospectively in 90 children with acute renal failure to intrinsic renal damage. The mean age at presentation was 8.1 years. Diagnosis and number of patients were as follows: Hemolytic uremic syndrome (HUS) in 32 patients, tubulo-interstitial nephritis in 19, idiopathic nephrotic syndrome in 10, IgA nephropathy on 9, membranoproliferative glomerulonephritis in 8, lupus in 5, poststreptococcal glomerulonephritis in 4, cortical necrosis in 1, Henoch Schoenlein purpura nephritis in 1 and anti-neutrophil cytoplasmic antibody associated glomerulonephritis in 1. Thirty-nine patients needed dialysis, but 36 of these were able to stop dialysis, 3 patients with HUS without gastrointestinal symptoms needed chronic dialysis. The mean follow-up period was 7.3 years from onset, and the the latest follow-up 82 patients had normal renal function, 3 showed chronic renal failure, 2 had regular dialysis, 2 had successful renal transplantation, an 1 had died due to heart failure. A poor outcome was associated with diffuse crescents and the presence of severe vascular changes. The early biopsy findings were very useful for the management of children with acute renal failure.

Acute Kidney Injury↗
PubMed1997

[A prospective controlled study of sairei-to in childhood IgA nephropathy with focal/minimal mesangial proliferation. Japanese Pediatric IgA Nephropathy Treatment Study Group].

To determine the effect of the Chinese herbal medicine, Sairei-to (TJ-114) in children with newly diagnosed IgA nephropathy showing focal/minimal mesangial proliferation, we undertook a prospective controlled study. One hundred and one patients were randomly assigned to receive Sairei-to for 2 years (group 1) or no drug for 2 years (group 2). Forty-six of the 50 patients in group 1 and 48 of the 51 patients in group 2 completed their trial. At entry, the two groups of patients did not differ in the clinical, laboratory and pathologic findings. At the end of the trial, urinary protein excretion and hematuria were significantly reduced in group 1, but were unchanged in group 2. Twenty-one group 1 patients (46%) had normal urine, but only 5 group 2 patients (10%) had normal urine at the end of the trial (p < 0.001). Blood pressure and creatinine clearance were normal at the end of the trial in all but one group 2 patient, who developed chronic renal failure. The present study demonstrates that 2-year Sairei-to treatment early in the course of disease is effective in children with IgA nephropathy showing focal/minimal mesangial proliferation.

Adolescent↗
PubMed1996

Thioredoxin: a redox-regulating cellular cofactor for glucocorticoid hormone action. Cross talk between endocrine control of stress response and cellular antioxidant defense system.

Adaptation to stress evokes a variety of biological responses, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and synthesis of a panel of stress-response proteins at cellular levels: for example, expression of thioredoxin (TRX) is significantly induced under oxidative conditions. Glucocorticoids, as a peripheral effector of the HPA axis, exert their actions via interaction with a ligand-inducible transcription factor glucocorticoid receptor (GR). However, how these stress responses coordinately regulate cellular metabolism is still unknown. In this study, we demonstrated that either antisense TRX expression or cellular treatment with H2O2 negatively modulates GR function and decreases glucocorticoid-inducible gene expression. Impaired cellular response to glucocorticoids is rescued by overexpression of TRX, most possibly through the functional replenishment of the GR. Moreover, not only the ligand binding domain but the DNA binding domain of the GR is also suggested to be a direct target of TRX. Together, we here present evidence showing that cellular glucocorticoid responsiveness is coordinately modulated by redox state and TRX level and propose that cross talk between neuroendocrine control of stress responses and cellular antioxidant systems may be essential for mammalian adaptation processes.

Animals↗
PubMed1996

Activation-induced expression of vascular permeability factor by human peripheral T cells: a non-radioisotopic semiquantitative reverse transcription-polymerase chain reaction assay.

Vascular permeability factor, also known as vascular endothelial growth factor (VPF/VEGF), is a disulfide-linked dimeric glycoprotein of about 40 kDa that enhances vascular permeability, induces chemotaxis and activation of monocytes/macrophages, and promotes growth of vascular endothelial cells. It has been reported that several tumor cell lines and normal cells produce VPF/VEGF. To examine the possibility of VPF/VEGF mRNA expression in human peripheral T cells and its mechanism(s) of regulation, we developed a non-radioisotopic semiquantitative reverse transcription-polymerase chain reaction (RT-PCR; VPF/VEGF, GAPDH co-amplification) assay which detects all species of VPF/VEGF mRNA alternative splicing products. T cells expressed negligible VPF/VEGF mRNA in the resting state. However, TPA markedly enhanced the expression of 121-, 165- and 189-amino-acid-containing isoforms of VPF/VEGF mRNA in T cells. Both CD4+ and CD8+ T cells expressed VPF/VEGF mRNA in response to TPA treatment. Moreover, T cell receptor stimulation with monoclonal anti-CD3 antibody with or without IL-1 beta enhanced VPF/VEGF mRNA expression in T cells. These findings suggest that T cell activation induces VPF/VEGF expression in the cells, resulting in induction of its biological activities.

Endothelial Growth Factors↗
PubMed1996

Hemodynamics in the colonic mucosa of rats with dextran sulfate-induced colitis in the early phase.

We investigated hemodynamics in the colonic mucosa of rats with experimental colitis induced by the administration of dextran sulfate sodium (DSS). As parameters of hemodynamics, we determined the indices of mucosal hemoglobin concentration (IHb) and mucosal oxygen saturation (ISO2), measured by reflectance spectrophotometry, and an index of colonic mucosal blood flow (Flow), measured by laser-Doppler flowmetry. In the ascending colon, each parameter was measured by a combination of these methods after 1, 3, 5, 7, and 10 days of DSS administration. Histopathological examination was also performed. IHb in the DSS group increased with time; on the 7th day, the value was 126.9 +/- 8.32, while that in the control group was 85.0 +/- 4.14, IHb in the DSS group being significantly increased (P < 0.02). ISO2 in the DSS group was lower than that in the control group, and on the 7th day, was significantly lower in the DSS group (25.7 +/- 1.34) than in the control group (33.4 +/- 1.77) (P < 0.01). No changes in Flow were observed in either the DSS or the control group during the administration period, and no significant difference in Flow was found between the two groups. On histopathological examination, we observed a time-dependent increase in the infiltration of inflammatory cells in the ascending colon of rats treated with DSS, but changes such as erosion and ulceration were not found in the superficial layer of the mucosa. No histopathological changes were found in the control animals. In the early phase of the experimental colitis, hemodynamic alterations in the colonic mucosa were already present at the time the slight histopathological changes developed. These observations seemed to indicate the involvement of hemodynamic alterations in the subsequent tissue injury.

Animals↗
PubMed1996

Relationship between serum and hepatic 7S fragments of type IV collagen in chronic liver disease.

We evaluated the mechanism of increased serum concentrations of the 7S fragment of the N-terminal domain of type IV collagen (7S collagen) in chronic liver disease. We measured the concentrations of hepatic-free and deposited 7S collagens after extraction with Tris-HCl buffer and bacterial collagenase, then compared them with the serum levels in 8 normal controls and 48 patients with chronic liver disease. The hepatic 7S collagen levels extracted with Tris-HCl buffer and collagenase accounted for 7% and 93%, respectively, of the total 7S collagen levels in normal controls. Both hepatic 7S collagen levels as well as serum levels increased in accordance with the progress of liver disease. Serum levels of 7S collagen showed a closer correlation with the hepatic 7S collagen levels extracted with Tris-HCl buffer (r = .822), compared with those extracted with collagenase (r = .382). On the other hand, the histological degrees of liver fibrosis were highly correlated with the hepatic collagenase-extracted 7S collagen levels (r = .822), compared with serum and the hepatic Tris-HCl buffer-extracted levels (r = .478 and r = .537, respectively). Although there was no difference in serum and hepatic 7S collagen levels between B and C viral patients, the serum and hepatic Tris-HCl buffer-extracted 7S collagen levels were higher in patients with alcoholic cirrhosis than patients with viral cirrhosis. However, the hepatic collagenase-extracted levels were similar in both groups. Gel filtration demonstrated that the serum and hepatic Tris-HCl buffer-extracted 7S collagens were mainly eluted in the macromolecular 7S collagen-reactive fraction in cirrhosis, whereas the hepatic collagenase-extracted 7S collagen was eluted in the authentic 7S collagen-reactive fraction. The results suggest that serum 7S collagen levels are not a particularly reliable measure of hepatic fibrosis but reflect the enhanced metabolism, especially synthesis of type IV collagen in the liver.

Adolescent↗
PubMed1996

Studies of retroorbital tissue xenografts from patients with Graves' ophthalmopathy in severe combined immunodeficient (SCID) mice: detection of thyroid-stimulating antibody.

The pathogenesis of Graves' ophthalmopathy (GO) is still unclear and the possible role of TSH receptor antibody in the development of GO is controversial. However, the recent availability of severe combined immunodeficient (SCID) mice has provided a means to study of human autoimmune thyroid disease in an in vivo environment. In the present study, we xenografted human retroorbital (RO) tissues from 9 patients with GO into 9 SCID mice and the autologous peripheral blood mononuclear cells (PBMC) from 5 of 9 GO patients were engrafted into 5 separate SCID mice to reconstitute the immunological environment of human GO. Mice blood samples were taken every 2 weeks for the measurements of human IgG, thyroglobulin antibody (Tg-Ab), thyroperoxidase (TPO)-Ab, thyroid-stimulating antibody (TSAb), and interferon-gamma (IFN-gamma). Eight weeks after xenografting, mice were killed; RO tissues were analyzed histologically, SCID mice with RO tissues from 2 of 9 GO patients produced human IgG peaking at 6-8 weeks after xenografting. TPO-Abs and TG-Abs were detectable in low titer in mice with RO tissue xenografts from 3/9 and 4/9 GO patients, respectively. The mean level of IFN-gamma in SCID mice with GO RO xenografts was higher than that of a control subject (RO tissue from a non-GO patient). TSAbs were actually produced from 7 of 9 mice xenografted with GO RO tissues, and reached their peaks at 2-8 weeks after xenografting; autologous PBMC (alone, without RO tissues)-engrafted SCID mice did not produce any detectable level of TSAb. The control mouse did not produce any detectable levels of human IgG, TPO-Ab, Tg-Ab, or TSAb. Immunohistochemical analysis of orbital mononuclear cell infiltrates revealed a predominance of T lymphocytes, with a small percentage of B lymphocytes in GO RO tissue graft. In conclusion, we have successfully reconstituted the SCID mice with human lymphocytes of RO tissues from patients with GO. Autoreactive B cell clones responsible for secreting TSAb exist in GO RO tissue and may be a key factor in the initiation and/or the progression of GO.

Adult↗
PubMed1996

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.

Animals↗
PubMed1996

IFN-gamma has a protective role against thyroid-specific autoantibody production in severe combined immunodeficient (SCID) mice xenografted with Graves' thyroid tissue.

We studied the effects of exogenous human IFN-gamma or neutralizing monoclonal antibody (mAb) to IFN-gamma on xenografted human Graves' thyroid tissue in severe combined immunodeficient (SCID) mice to investigate a possible role of IFN-gamma in the pathogenesis of human Graves' disease. Human thyroid tissues from four patients with Graves' disease were xenografted into SCID mice. Two weeks after xenografting, mice were divided into three groups with human IgG levels similar to each other. Mice in the first group were treated with human IFN-gamma daily for 6 weeks; mice in the second (similar) group were treated with an mAb to IFN-gamma; mice in the third group were given mouse IgG only (control group). Blood samples were taken every 2 weeks for human IgG and thyroid-specific autoantibodies (Tg-Ab, TPO-Ab, and thyroid-stimulating antibody). After 6 weeks' treatment, mice were killed, and the thyroid xenograft was examined for thyrocyte HLA-DR expression. Human IgGs were produced equally in all three groups; mice treated with IFN-gamma showed significantly lower amounts of thyroid autoantibodies than those in the control group. Thyrocyte HLA-DR expression was markedly increased in xenografts from mice with IFN-gamma administration. On the other hand, anti-IFN-gamma mAb injection caused only slight suppression of HLA-DR expression on xenografted thyroid cells. In conclusion, IFN-gamma may down-regulate the production of thyroid-specific autoantibodies but not human IgG, at least under these circumstances; there thus may be specific inhibitory effects of IFN-gamma against thyroid-specific autoantibody production of intrathyroidal plasma cells, and this animal model may help to elucidate the possible role of cytokines in the pathogenesis of Graves' disease.

Animals↗