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Biomedical subjects

Y C Kong

Publications and source records attributed to Y C Kong.

At least 19 recordsLinked to original sources
PubMed1992

Circumvention of the induction of resistance in murine experimental autoimmune thyroiditis by recombinant IL-1 beta.

Murine experimental autoimmune thyroiditis (EAT) is induced in genetically susceptible mice by immunization with mouse thyroglobulin (MTg). We have previously shown that raising the level of circulatory MTg for greater than or equal to 2 to 3 days, by the i.v. injection of soluble MTg or the infusion of thyroid-stimulating hormone, rendered these mice resistant to subsequent EAT induction. The Ag-specific resistance was mediated by CD4+ Ts cells, and the induction of unresponsiveness could be interfered with by injecting the T cell adjuvant poly(A).poly(U) 3 h after MTg pretreatment. To dissect further the cytokine signals involved in circumventing the induction of resistance, the effect of human rIL-1 beta was examined. As with poly(A).poly(U), mice given 4000 or 10,000 U or rIL-1 beta 3 h after deaggregated MTg (dMTg) were not resistant to EAT induced with MTg and adjuvant. Moreover, mice given 90,000 U or rIL-1 beta after dMTg and then immunized displayed very severe thyroiditis, strong in vitro proliferative response, and high antibody titers, compared with immunized controls, indicating a dose-dependent effect of rIL-1 beta. The intermediate dose of 10,000 U or rIL-1 beta was selected to determine the importance of time interval between dMTg and rIL-1 beta administration. Interference with the induction of suppression was more efficacious when rIL-1 beta was given at 3 h than at 24 h, but at 24 h it was no more effective than 4000 U given at this interval. In contrast, mice given 10,000 U of rIL-1 beta 3 h before dMTg and then challenged developed MTg antibodies but little thyroiditis, demonstrating that the interference with suppression of autoantibody responses can occur without altering the induction of suppression of thyroiditis. The injection of rIL-1 beta also led to a sharp but transient rise in serum IL-6. The short t1/2 of IL-6 suggests that any role played by IL-6 would require critical timing. Murine rIL-2 given at 1 and 2 days after dMTg had a minimal effect on induced resistance. Lastly, immunization of dMTg-pretreated mice with MTg and rIL-1 beta did not induce EAT, demonstrating that rIL-1 beta could not interfere with established suppression. Thus, the intervention by rIL-1 beta in MTg-induced suppression occurs at a critical time, early after the injection of dMTg but before the establishment of resistance.

Animals↗
PubMed1992

Resistance to experimental autoimmune thyroiditis is correlated with the duration of raised thyroglobulin levels.

We have used the mouse model of experimental autoimmune thyroiditis (EAT) to examine the hypothesis that the strengthening of self-tolerance to thyroglobulin by exogenous mouse thyroglobulin (MTg) or stimulation of endogenous MTg secretion by thyroid-stimulating hormone (TSH) is correlated with the length of time MTg rises above the normal range. Bacterial lipopolysaccharide (LPS) treatment increases the initial half-life of MTg from about 3 hr to about 5 hr, probably interfering with its clearance by the mononuclear phagocytic (reticuloendothelial) system. By pretreating mice with LPS, a subtolerogenic MTg dose is rendered tolerogenic. Similarly the effect of TSH infusion by osmotic minipumps, which stimulates MTg secretion and also strengthens tolerance to MTg, can be enhanced by injecting LPS shortly after pump implantation. The resulting increase in MTg level (due to delayed clearance of MTg) is greater than that from TSH alone and suppresses further the animals' susceptibility to disease induction by MTg and adjuvant. Moreover, resistance following pretreatment with LPS and subtolerogenic MTg is mediated by CD4+ suppressor T cells, as shown recently for the suppression in mice given high doses of tolerogenic MTg. These experiments are in full agreement with the hypothesis and confirm that small increases in circulating MTg concentrations, which could occur physiologically, can be effective in protecting against EAT induction.

Animals↗
PubMed1991

Anti-implantation activity of S(-)- and R(+)-camphor-yuehchukene in rats.

(+/-)-Yuehchukene is a dimeric indole alkaloid with potent anti-implantation activity in rats. Since (+/-)-yuehchukene occurs in nature as a racemate, it would be desirable to find out which enantiometer is the bio-active form. To this end, S(-)-camphor-yuehchukene and R(+)-camphor-yuehchukene were synthesised and tested in three bioassay models. It was found that the R(+) enantiomer was the active form. It was equipotent with (+/-)-yuehchukene in both anti-implantation and estrogenic activity tests. It seems fair to conclude that both activities reside in the same molecule.

Alkaloids↗
PubMed1991

Suppression in murine experimental autoimmune thyroiditis: in vivo inhibition of CD4+ T cell-mediated resistance by a nondepleting rat CD4 monoclonal antibody.

Genetically susceptible mice become resistant to experimental autoimmune thyroiditis (EAT) induction with mouse thyroglobulin (MTg) and lipopolysaccharide after pretreatment with deaggregated MTg (dMTg). Recent work showed this suppression to be mediated by CD4+ suppressor T cells (Ts). To study Ts action in vivo, we used a rat IgG2a monoclonal antibody (mAb), YTS 177.9, which modulates CD4 antigen in vivo without depleting CD4+ cells. Initial studies showed that after two 1-mg doses of mAb 7 days apart, extensive CD4 antigen modulation of peripheral blood leukocytes occurred within 4 days. Mice given CD4 mAb 24 hr before dMTg (2 doses, 7 days apart) were resistant to EAT induction when immunized with MTg and LPS 20 days later. Also, anti-rat IgG2a titers were reduced following challenge with heat-aggregated rat IgG2a compared to controls. Subsequent analysis of serum in CD4 mAb-treated animals revealed that mAb was present in the circulation for 14 days. Moreover, mice given CD4 mAb and dMTg, then challenged after only 10 days, when CD4 mAb was still circulating, developed a significantly higher incidence of thyroid damage than controls. These findings suggest that modulation of CD4 antigen does not interfere with Ts activation, but the presence of CD4 mAb, at the time of autoantigenic challenge, can interfere with tolerance to EAT induction. Thus, the direct relationship between the presence of CD4 mAb and inhibition of EAT suppression implicates a role for CD4 molecules in the mediation of suppression.

Animals↗
PubMed1991

Synergism between mouse thyroglobulin- and vaccination-induced suppressor mechanisms in murine experimental autoimmune thyroiditis.

Previous studies have shown that genetically susceptible mice can be rendered resistant to the induction of experimental autoimmune thyroiditis (EAT) by pretreatment with deaggregated mouse thyroglobulin (dMTg). This resistance is mediated by CD4+ suppressor T cells (Ts) which suppress the afferent/inductive phase of EAT. Recent work has also shown that resistance to EAT can be achieved by vaccination with irradiated spleen cells previously primed in vivo with MTg and cultured in vitro with MTg (gamma SC). The gamma SC-induced resistance also inhibits the afferent phase of EAT but is mediated by both CD4+ and CD8+ Ts. To determine if dMTg- and gamma SC-induced suppression can cooperate to prevent EAT, we pretreated mice with suboptimal doses of dMTg and gamma SC before challenge with MTg and adjuvant. Mice receiving dMTg or gamma SC only showed suppressed in vitro response to MTg, but the development of thyroid lesions was unaltered. However, mice given one or two subtolerogenic doses of dMTg followed by gamma SC not only showed suppressed in vitro response to MTg, but also little or no thyroiditis, indicating cooperation between these two mechanisms. The cooperation was not reciprocal since reversing the order, giving gamma SC first followed by dMTg, was not effective in suppressing EAT. Thus, suppressor mechanisms activated by pretreatment with dMTg and gamma SC can act synergistically to suppress EAT induction; the two mechanisms may cooperate in vivo to maintain self-tolerance provided that MTg-specific CD4+ Ts are initially activated.

Animals↗
PubMed1991

In vivo evidence for CD4+ and CD8+ suppressor T cells in vaccination-induced suppression of murine experimental autoimmune thyroiditis.

In several experimental autoimmune diseases, including experimental autoimmune thyroiditis (EAT), vaccination with attenuated autoantigen-specific T cells has provided protection against subsequent induction of disease. However, the mechanism(s) of vaccination-induced suppression remains to be clarified. Since we have previously shown that suppression generated by pretreatment with mouse thyroglobulin (MTg) or thyroid-stimulating hormone in EAT is mediated by CD4+, not CD8+, suppressor T cells, we examined the role of T cell subsets in vaccination-induced suppression of EAT. Mice were vaccinated with irradiated, MTg-primed, and MTg-activated spleen cells and then challenged. Pretreatment with these cells suppressed EAT induced by immunization with MTg and adjuvant, but not by adoptive transfer of thyroiditogenic cells, suggesting a mechanism of afferent suppression. The activation of suppressor mechanisms did not require CD8+ cells, since mice depleted of CD8+ cells before vaccination showed reduced EAT comparable to control vaccinated mice. Furthermore, depletion of either the CD4+ or the CD8+ subset after vaccination did not significantly abrogate suppression. However, suppression was eliminated by the depletion of both CD4+ and CD8+ cells in vaccinated mice. These results provide evidence for the cooperative effects of CD4+ and CD8+ T cells in vaccination-induced suppression of EAT.

Animals↗
PubMed1990

Induction of tolerance in peripheral T cells with monoclonal antibodies.

Our goal has been to develop ways to tolerize the mature immune system to any defined antigen. In this report we show that peripheral (post-thymic) T cells of mice can become tolerant to a range of antigens (human and rat immunoglobulins, and bone marrow and skin grafts that differ at multiple minor transplantation antigens). In the case of human gamma globulin (HGG), this required that the antigen be given under the cover of a short course of non-depleting anti-CD4 antibody, while for tolerance to skin and marrow grafts anti-CD8 antibody was also required. Tolerance to HGG could be reinforced by repeated injections of HGG, but was lost in the absence of any further exposure to antigen. This reversal of tolerance with time was due to new T cells being exported from the thymus, as it was not observed in tolerized, adult thymectomized mice. In contrast, tolerance to marrow and skin grafts was permanent, presumably because the established grafts acted as a continuous source of antigen to reinforce the tolerant state. Tolerance could not be broken by the infusion of unprimed spleen cells and in one example (tolerance to Mls-1a) there was clear evidence that specific peripheral T cells were anergic. We propose that anergic cells may themselves participate in reinforcing the tolerant state by competing at sites of antigen presentation.

Animals↗
PubMed1990

In situ analysis of T cell subset composition in experimental autoimmune thyroiditis after adoptive transfer of activated spleen cells.

T cells from genetically susceptible mice developing experimental autoimmune thyroiditis (EAT) proliferate in response to restimulation with mouse thyroglobulin (MTg) in vitro. The in vitro-activated cells adoptively transfer EAT as well as differentiate into cells cytotoxic for syngeneic thyroid monolayers. To examine the kinetics of T cell subset infiltration and distribution in situ after adoptive transfer, we applied the avidin-biotin-peroxidase labeling technique to thyroid sections, utilizing rat monoclonal antibodies followed by a biotinylated rabbit anti-rat antibody. Female CBA donor mice were immunized with MTg and lipopolysaccharide. Their spleen cells were obtained 7 days later, cultured with MTg, and transferred into recipient mice. The thyroids were removed on Days 7, 10, and 14 after transfer and serially sectioned. The early phase of transferred EAT showed a higher percentage of L3T4+ cells compared to Lyt-2+ cells, yielding a ratio of 2.3 and total T cells of about 35%. By Day 10, both T cell subsets had increased to a total of about 56%. However, the relative increase was greater in the Lyt-2+ subset; the nearly doubled percentage was statistically significant, resulting in a downward shift in the subset ratio to 1.7. Little change in the in situ distribution was seen on Day 14. The percentages of F4/80+ (macrophage) population in lesions examined on Days 10 and 14 were fairly constant and B cell involvement was minimal. These findings illustrate the pathogenic role of both T cell subsets in adoptively transferred EAT and the time-dependent changes in their relative proportions leading to thyroid gland destruction.

Animals↗
PubMed1990

Suppression in experimental autoimmune thyroiditis: the role of unique and shared determinants on mouse thyroglobulin in self-tolerance.

Previous studies have shown that T cells from mice genetically susceptible to experimental autoimmune thyroiditis (EAT) recognize determinants shared between mouse thyroglobulin (Tg) and heterologous Tgs. Some shared determinants are thyroiditogenic; lymphocytes from mice immunized with mouse Tg (MTg) or human Tg (HTg) and reciprocally restimulated in vitro with either Tg can transfer EAT. Studies on the mechanisms of self-tolerance have shown that pretreatment with soluble MTg suppresses in vitro proliferation to MTg and EAT induction with MTg. To determine the role of share epitopes in maintaining tolerance, mice were pretreated with soluble HTg and immunized with HTg or MTg and adjuvant. Cells from HTg-pretreated. HTg-immunized mice showed suppressed in vitro proliferative response to HTg. Following MTg immunization, the cells showed suppressed in vitro response to MTg. However, in contrast to MTg pretreatment, the subsequent development of EAT in vivo was unaltered in severity following HTg pretreatment. Thus, determinants shared between HTg and MTg can induce suppression of in vitro responses to HTg and MTg, but not inhibit the onset of thyroiditis, suggesting that T cells recognizing MTg-unique epitopes expanded to mediate thyroiditis. We conclude that recognition of both unique epitopes expanded to mediate thyroiditis. We conclude that recognition of both unique and shared epitopes on MTg are essential for the overall maintenance of self-tolerance.

Animals↗
PubMed1989

Depletion of L3T4+ and Lyt-2+ cells by rat monoclonal antibodies alters the development of adoptively transferred experimental autoimmune thyroiditis.

To delineate the contribution of L3T4+ and Lyt-2+ cells in the pathogenesis of experimental autoimmune thyroiditis (EAT), synergistic pairs of monoclonal antibodies (mAb) to the T cell subsets were used in conjunction with the adoptive transfer of mouse thyroglobulin (MTg)-activated cells from immunized mice. Initial experiments verified the important role of L3T4+ cells in the transfer of EAT. Subsequent experiments pointed to the relative contribution of both L3T4+ and Lyt-2+ cells, depending on the stage and extent of disease development. Treatment during disease with L3T4, but not Lyt-2, mAb alone significantly reduced thyroiditis. However, in situ analysis of the cellular infiltrate in thyroid sections revealed that, after treatment with mAb, the appropriate subset was eliminated without altering the amount of the other subset in the remaining lesion. In addition, treatment during severe thyroiditis following the transfer of MTg-activated lymph node cells showed that Lyt-2 mAb alone also reduced thyroid infiltration. When the recipients were pretreated with either pair of mAb before transfer, disease development was only moderately affected. We conclude that (i) donor L3T4+ cells are the primary cells responsible for the initial transfer and development of thyroiditis; and (ii) previous in vitro cytotoxicity data, plus current monoclonal antibody treatment of disease and in situ analysis, further implicate a role for Lyt-2+ cells in EAT pathogenesis.

Animals↗
PubMed1989

Long-term observation and effect of age on induction of experimental autoimmune thyroiditis in susceptible and resistant mice.

After induction of experimental autoimmune thyroiditis (EAT) in mice, long-term observation on both the severity of thyroiditis and antibody formation against mouse thyroglobulin (MTg) was carried out over a period of 18 months. In EAT-susceptible strains (CBA, C3H/Anf), both the severity of thyroiditis and MTg antibody production continued for a long term. In EAT-resistant mice (BALB/c), thyroiditis remained minimal, if present, and the low antibody response to MTg became negligible. On the other hand, aging had a prominent effect on the EAT induction in susceptible mice; both MTg antibody response and thyroid infiltration were markedly reduced. These data were well correlated with reduced antibody formation against sheep red blood cells. Young and old mice were further compared as donors or recipients in adoptive transfer of concanavalin A-stimulated cells. Lymph node cells from either young or old MTg-immunized mice transferred appreciable thyroiditis to normal young and old recipient mice. However, similarly treated spleen cells from MTg-immunized old mice responded more poorly to in vitro stimulation with mitogens or MTg and transferred thyroiditis to very few normal young or old mice.

Aging↗
PubMed1989

In situ kinetic analysis of thyroid lymphocyte infiltrate in mice developing experimental autoimmune thyroiditis.

L3T4+ T cells from genetically susceptible mice developing experimental autoimmune thyroiditis (EAT) were shown earlier to proliferate in response to restimulation with mouse thyroglobulin (MTg) in vitro and to mediate the adoptive transfer of EAT, whereas Lyt-2+ cells differentiated in vitro into cells cytotoxic for thyroid monolayers. Leukocyte suspensions from disrupted thyroid glands examined on Days 13-21 after immunization revealed the accumulation of both T cell subsets in the infiltrate at varying ratios. To characterize the in situ kinetics of cellular infiltration in chronic EAT, we extended the observation intervals after immunization to include Days 21 to 42. The leukocytes in thyroid sections were labeled immunohistochemically first with rat monoclonal antibodies to L3T4, Lyt-2, Thy-1, k light chain, or F4/80 macrophage antigen, then with biotinylated anti-rat IgG, utilizing the avidin-biotin-peroxidase technique. Throughout the 21- to 42-day interval, no significant variations were detected in the percentages of L3T4+ subset, but those of Lyt-2+ cells increased and then declined. The shift in the L3T4+:Lyt-2+ ratio, down from 2.4 to 1.6 and then up to 3.0, was directly related to changes in the Lyt-2+ subpopulation. The F4/80+ and B cell populations changed little during this period. These findings illustrate the changing kinetics of T cell subsets in situ in the development and perpetuation of EAT and MTg-immunized mice.

Animals↗
PubMed1989

Antifertility principle of Ruta graveolens.

Chloroform extracts of the root, stem and leaf of Ruta graveolens L. showed significant anti-fertility activity in rats when administered intragastrically on days 1-10 post-coitum. Fractionation of the extracts led to the isolation of chalepensin as the active component with some toxicity. Time-dosing experiments demonstrated that chalepensin acts at the early stages of pregnancy. It is not clear at this stage if the anti-fertility effect is a direct manifestation of chalepensin toxicity.

5-Methoxypsoralen↗
PubMed1989

Purification and properties of glycerol:NADP+ 2-oxidoreductase from Schizosaccharomyces pombe.

Glycerol:NADP+ 2-oxidoreductase (EC 1.1.1.156) was isolated from Schizosaccharomyces pombe, purified and characterized. It had an Mr of 57,000, and SDS-PAGE revealed two polypeptides, of Mr 25,000 and 30,000. Its coenzyme requirement was satisfied exclusively by NADP. The pH optimum for glycerol oxidation was 9.5, for dihydroxyacetone reduction 6.0. Rates of oxidation with some structurally related diols were three- to six-fold lower than for glycerol, while glyceraldehyde and other carbonyl compounds showed negligible rates of reduction. Neither monovalent nor divalent cations activated the enzyme. Apparent Km and Vmax values were determined. The enzyme is similar to glycerol dehydrogenases isolated from Mucor javanicus and from Dunaliella parva but differs considerably from the glycerol:NAD+ 2-oxidoreductase of S. pombe.

Coenzymes↗
PubMed1987

Resistance to experimental autoimmune thyroiditis induced by physiologic manipulation of thyroglobulin level.

The role of circulatory mouse thyroglobulin (MTg) level in activating mechanisms suppressive to induction of experimental autoimmune thyroiditis (EAT) was studied by two regimens to strengthen normal maintenance of self-tolerance in genetically susceptible mice. One was to administer graded doses of exogenous MTg either 7 days apart or daily for 10 days and then challenge the animals with MTg + LPS. The other was to infuse TSH via an osmotic pump for 7 days. The steady TSH infusion for 7 days resulted in an increase in MTg level peaking on Day 3. Such kinetics of MTg concentration in response to TSH coincided with enhanced resistance to EAT induction. After an initial rapid clearance rate of t1/2 of 3 hr, tolerogenic doses of exogenous MTg sustained similar levels for 2-3 days. In contrast, subtolerogenic doses declined to baseline levels in 2 days or less. Clearance can be best explained by a two-compartment model for distribution with an initial alpha phase (t1/2 about 3 hr), followed by a beta phase (t1/2 about 10 hr). We conclude that, for the prevention of EAT induction in the presence of potent adjuvants (CFA or LPS), a threshold, but above baseline, level of either exogenous or endogenous MTg, represented by the beta phase, is required for a critical period (greater than 2-3 days) to activate suppressor mechanisms over and above homeostatic regulation. Whether MTg concentration raised by TSH (TRH) administration activates suppressor T cells as observed after the injection of a tolerogenic dose of MTg remains to be determined.

Animals↗
PubMed1987

Evidence that epidermal growth factor is present in swiftlet's (Collocalia) nest.

1. An epidermal growth factor (EGF)-like activity was detected and partially purified from swiftlet's nest extract. 2. The partially purified EGF-like activity was able to (a) generate competitive binding curves parallel to the standard curves in radioreceptor assay and (b) stimulate thymidine incorporation in quiescent culture of 3T3 fibroblasts and the latter activity can be suppressed by mouse EGF antibody. 3. Partial characterization of the EGF-like activity in terms of pI, molecular weight and its behavior on gel filtration column suggest that it bears similar physical properties to the EGFs isolated from the mouse and the shrew.

Animals↗
PubMed1987

The aacA-aphD gentamicin and kanamycin resistance determinant of Tn4001 from Staphylococcus aureus: expression and nucleotide sequence analysis.

The aacA-aphD aminoglycoside resistance determinant of the Staphylococcus aureus transposon Tn4001, which specifies resistance to gentamicin, tobramycin and kanamycin, has been cloned and shown to express these resistances in Escherichia coli. The determinant encoded a single protein with an apparent size of 59 kDa which specified both aminoglycoside acetyltransferase [AAC(6')] and aminoglycoside phosphotransferase [APH(2")] activities. Nucleotide sequence analysis of the determinant showed it to be capable of encoding a 479-amino-acid protein of 56.9 kDa. analysis of Tn1725 insertion mutants of the determinant indicated that resistance to tobramycin and kanamycin is due to the AAC activity specified by, approximately, the first 170 amino acids of the predicted protein sequence and is consistent with the gentamicin resistance, specified by the APH activity, being encoded within the C-terminal region of the protein. Comparison of the C-terminal end of the predicted amino acid sequence with the reported sequences of 13 APHs and a viomycin phosphotransferase revealed a region which is highly conserved among these phosphotransferases.

Amino Acid Sequence↗