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F S Wong

Publications and source records attributed to F S Wong.

At least 37 records · Page 2Linked to original sources
PubMed1999

Designing and maintaining the mature TCR repertoire: the continuum of self-peptide:self-MHC complex recognition.

Peripheral T cell maintenance requires a survival signal delivered upon T cell receptor (TCR)-major histocompatibility complex (MHC) molecule interaction. Since self-peptides play a critical role in the intrathymic positive selection of the mature TCR repertoire, we hypothesized an equally important role in T cell persistence. We used mice with a normal expression of MHC class II molecules but a restricted self-peptide complexity (H-2M alpha-/-) to show that an MHC class II-restricted T cell specificity that displays a deficient positive selection in the H-2M alpha-/- thymus shows an impaired persistence after adoptive transfer in H-2M alpha-/- recipients. Finally, a wild-type CD4+ TCR repertoire is incompletely maintained in H-2M alpha-/- recipients. These observations suggest that, similar to intrathymic positive selection, the maintenance of the mature TCR repertoire relies on the recognition of self-peptide:self-MHC complexes.

Adoptive Transfer↗
PubMed1999

Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library.

Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed at an early age by an immune process that involves both CD4 and CD8 T lymphocytes. The identification of autoantigens in diabetes is very important for the design of antigen-specific immunotherapy. By screening a pancreatic islet cDNA library, we have identified the autoantigen recognized by highly pathogenic CD8 T cells in the non-obese diabetic mouse, one of the best animal models for human diabetes. This is the first identification, to our knowledge, of a CD8 T-cell epitope in an autoimmune disease. The peptide recognized by the cells is in the same region of the insulin B chain as the epitope recognized by previously isolated pathogenic CD4 T cells. This has very important implications for the potential use of insulin in preventative therapy.

Amino Acid Sequence↗
PubMed1999

Transgenes and knockout mutations in animal models of type 1 diabetes and multiple sclerosis.

In this article, we will examine the roles of transgenic and knockout animals that aid us in understanding two autoimmune diseases-type 1 (insulin-dependent) diabetes and multiple sclerosis. The first sections will focus on studies in type 1 diabetes to show how genetically altered animals have given insight into the role of various immune cell types, autoantigens, co-stimulatory molecules, cytokines and, finally, the role of various effector pathways in the pathogenesis of diabetes. The second section concentrating on the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), will show how animals that express a T-cell receptor derived from a clone able to cause disease have given insight into the pathogenesis of EAE.

Animals↗
PubMed1998

Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8-restricted CD4(+) T cells from human DQ transgenic mice.

Insulin-dependent diabetes mellitus in humans is linked with specific HLA class II genes, e.g., HLA-DQA1*0301/ DQB1*0302 (DQ8). To investigate the roles of HLA-DQ8 molecules and glutamic acid decarboxylase (GAD) in disease development, we generated DQ8(+)/I-Abo transgenic mice expressing functional HLA-DQ8 molecules and devoid of endogenous mouse class II. DQ8(+)/I-Abo mice produced antigen-specific antibodies and formed germinal centers after immunization with GAD65 peptides. Two GAD peptide-specific (247-266 and 509-528), DQ8 restricted Th1 CD4(+) T cell lines, were generated from immunized DQ8(+)/I-Abo mice. They induced severe insulitis after adoptive transfer into transgene positive (but not negative) mice who were treated with a very low dose of streptozotocin that alone caused no apparent islet pathology. In addition to CD4, islet mRNA from these mice also showed expression of CD8, IFNgamma, TNFalpha, Fas, and Fas ligand. Our data suggest that a mild islet insult in the presence of HLA-DQ8 bearing antigen-presenting cells promotes infiltration of GAD peptide reactive T cells into the islet.

Animals↗
PubMed1998

The role of lymphocyte subsets in accelerated diabetes in nonobese diabetic-rat insulin promoter-B7-1 (NOD-RIP-B7-1) mice.

B7-1 transgene expression on the pancreatic islets in nonobese diabetic (NOD) mice leads to accelerated diabetes, with >50% of animals developing diabetes before 12 wk of age. The expression of B7-1 directly on the pancreatic beta cells, which do not normally express costimulator molecules, converts the cells into effective antigen-presenting cells leading to an intensified autoimmune attack. The pancreatic islet infiltrate in diabetic mice consists of CD8 T cells, CD4 T cells, and B cells, similar to diabetic nontransgenic NOD mice. To elucidate the relative importance of each of the subsets of cells, the NOD-rat insulin promoter (RIP)-B7-1 animals were crossed with NOD.beta2microglobulin -/- mice which lack major histocompatibility complex class I molecules and are deficient in peripheral CD8 T cells, NOD.CD4 -/- mice which lack T cells expressing CD4, and NOD.muMT -/- mice which lack B220-positive B cells. These experiments showed that both CD4 and CD8 T cells were necessary for the accelerated onset of diabetes, but that B cells, which are needed for diabetes to occur in normal NOD mice, are not required. It is possible that B lymphocytes play an important role in the provision of costimulation in NOD mice which is unnecessary in the NOD-RIP-B7-1 transgenic mice.

Adoptive Transfer↗
PubMed1998

Primary gamma delta cell clones can be defined phenotypically and functionally as Th1/Th2 cells and illustrate the association of CD4 with Th2 differentiation.

The division of CD4+ alpha beta T cells into Th1 and Th2 subsets has become an established and important paradigm. The respective activities of these subsets appear to have profound effects on the course of infectious and autoimmune diseases. It is believed that specific programs of differentiation induce the commitment of an uncommitted Th0 precursor cell to Th1 or Th2. A component of these programs is hypothesized to be the nature of MHC-peptide antigen presentation to the alpha beta T cell. It has heretofore remained uncertain whether a Th1/Th2 classification likewise defines, at the clonal level, gamma delta T cells. Such cells do not, as a general rule, express either CD4 or CD8 alpha beta, and they do not commonly recognize peptide-MHC. In this report, gamma delta cell clones are described that conform strikingly to the Th1/Th2 classification, both by cytokine expression and by functional activities of the clones in vitro and in vivo. Provocatively, both the gamma delta cell clones and primary gamma delta cells in vivo showed a strong association of the Th2 phenotype with CD4 expression. These results are discussed with regard to the immunoregulatory role that is increasingly emerging for gamma delta cells.

Amino Acid Sequence↗
PubMed1998

GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice.

Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo. To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding Vbeta2 and Vbeta12. 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543. After antigen-specific stimulation, 5A T cells secrete IFNgamma and TNFalpha/beta, but not IL-4. They are also cytotoxic against NOD-derived hybridoma cells (expressing I-Ag7) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice. Diabetes occurred in 83% of the mice. We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides. Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM.

Adoptive Transfer↗
PubMed1998

A novel method for concurrent visualization of immunostain under light and electron microscopy in pancreatic islets.

We developed a simple method employing the use of flat-embedding techniques on thick frozen sections which allows correlation of light and electron microscopic immunohistochemistry. This method has been particularly useful in visualization of pancreas sections, an adaptation especially important because this tissue is not amenable to conventional vibratome sectioning. In this study we demonstrate the use of this technique to examine the same tissue section at the light and the electron microscopic level while maintaining morphology.

Animals↗
PubMed1998

Determination of mineral concentration in dental enamel from X-ray attenuation measurements.

The mineral content of dental enamel is commonly measured by X-ray attenuation experiments. Most studies have used contact microradiography in which intensities are measured with photographic film which is convenient and gives high spatial resolution. However photon counting intensity measurements are to be preferred in many experiments (longitudinal and scanning microradiography, and microtomography), as illustrated here, because they have a larger dynamic range and greater sensitivity to small intensity changes. Additionally, the detector and specimen are well separated which allows the pseudo-continuous study of de- and remineralization. The mineral content is often quoted as 95 wt% or 87 vol% hydroxyapatite for permanent human enamel. This determination from attenuation experiments requires accurate values of elemental mass attenuation coefficients and a number of assumptions. The effects of possible choices of these are considered and it is shown that the most important is the density of enamel mineral used in conversion of wt% to vol%. If the density is taken as 2.99 g cm(-3), as recently suggested (J.C. Elliott, Dental Enamel, Ciba Foundation Symposium 205, Wiley, Chichester, pp. 54-72, 1997), instead of 3.15 g cm(-3) as for hydroxyapatite, the calculated vol% is approximately 93 instead of approximately 87.

Dental Enamel↗
PubMed1997

Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience.

PURPOSE/OBJECTIVE: To evaluate the feasibility, response rates, and toxicity of a Phase II study using targeted supradose cisplatin and concurrent radiation therapy in unresectable Stage III-IV head and neck squamous cell carcinoma. METHODS AND MATERIALS: Sixty patients presenting between 6/93-9/94 were enrolled, 44 (73%) of whom had T4 and/or N2-N3 nodal disease. All patients were treated with rapid targeted superselective intraarterial infusions of cisplatin (150 mg/m2 weekly x 4) and simultaneous sodium thiosulfate intravenously (9 g/m2) for systemic neutralization of cisplatin. Concurrent (day 1) daily radiation therapy was delivered to the primary tumor and overt nodal disease to 66-74 Gy while the uninvolved lower neck received 50 Gy, at 2.0 Gy/fraction. RESULTS: Fifty-one (85%) patients completed the full RADPLAT protocol as planned. Fifty-seven of 60 patients were evaluable for response. Histological (n = 50) or clinical (n = 7) assessment of primary site revealed a complete response (CR) in 52 patients, partial response (PR) in 4, and stable disease (SD) in 1. Of the 40 patients presenting with nodal metastases, pathological (n = 31) or clinical (n = 6) assessment revealed a CR in 25, PR in 11, and SD in 1, while 3 were unevaluable. Overall, for both primary site and nodal disease, CR was attained in 44 (75%), PR in 12 (23%), and SD in 1 (2%) of the 57 evaluable patients. Only 2 (4%) of 57 evaluable patients have recurred above the clavicle, 1 in the primary site and 1 in the regional lymph nodes. Twelve patients (23%) have failed in distant sites. Grade III/VI toxicity has included gastrointestinal in 6, hematologic in 6, mucosal in 12, vascular in 4, and neurological in 4 patients. CONCLUSION: Concurrent radiation therapy and targeted supradose cisplatin (i.e., RADPLAT) can be safely delivered with high response rates and excellent loco-regional control in advanced Stage III/IV head and neck squamous cell carcinoma.

Adult↗
PubMed1997

The role of Fas in autoimmune diabetes.

Immunologically privileged sites express Fas ligand (FasL), which protects them from attack by activated T cells that express Fas and die upon contact with FasL. In an attempt to protect nonobese diabetic mice (NOD) from autoimmune diabetes, we made FasL transgenic NOD mice using the beta cell-specific rat insulin-1 promoter. Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of beta cells upon T cell-mediated induction of Fas. Fas-negative NOD(lpr/lpr) animals were resistant to diabetogenic T cells and to spontaneous diabetes. Thus, induction of Fas expression on beta cells and their subsequent destruction constitutes the main pathogenic mechanism in autoimmune diabetes.

Animals↗
PubMed1997

Planning future general anaesthetic services in paediatric dentistry on the basis of evidence: an analysis of children treated in the Day Stay Centre at the Royal Hospitals NHS Trust, London, between 1985-95.

This study aimed to provide evidence for future planning of general anaesthetic services in Paediatric Dentistry. An audit was carried out on children (< or = 17 years) with special needs who were treated under general anaesthesia in the Day Stay Centre at The Royal Hospitals NHS Trust, London, between 1985-95. During these years, 586 child patients were treated, of which 350 had medical complications and/or mental disabilities. Although the number of peri-operative admissions were low (11 planned and 9 emergency), it highlighted the necessity for these patients to be treated in a hospital. Comprehensive dental treatments were carried out which included 1630 deciduous and 596 permanent tooth restorations, and 1382 deciduous and 261 permanent tooth extractions. These patients had follow-up preventive support in the Dental Institute and the readmission rate for further dental treatment under general anaesthesia was low (14 per cent). Comparing the results between 1985-87, 1988-91 and 1992-95 periods, there was a trend for more patients, travelling longer distances, to be treated in the latter periods. It is suggested that more centres with appropriate equipment and trained staff need to be established to meet the increased demand.

Adolescent↗
PubMed1997

Theoretical explanation of the relationship between backscattered electron and x-ray linear attenuation coefficients in calcified tissues.

X-ray absorption and backscattered electron (BSE) microscopies are two commonly used techniques for estimating mineral contents in calcified tissues. The resolution in BSE images is usually higher than in x-ray images, but due to the previous lack of good standards to quantify the grey levels in BSE images of bones and teeth, x-ray microtomography (XMT) images of the same specimens have been used for calibration. However, the physics of these two techniques is different: for a specimen with a given composition, the x-ray linear attenuation coefficient is proportional to density, but there is no such relation with the BSE coefficient. To understand the reason that this calibration appears to be valid, the behaviour of simulated bone samples was investigated. In this, the bone samples were modelled as having three phases: hydroxyapatite (Ca10(PO4)6(OH)2), protein, and void (either empty or completely filled with polymethylmethacrylate (PMMA), a resin which is usually used for embedding bones and teeth in microscopic studies). The x-ray linear attenuation coefficients (calculated using published data) and the BSE coefficients (calculated using Monte Carlo simulation) were compared for samples of various phase proportions. It was found that the BSE coefficient correlated only with the x-ray attenuation coefficient for samples with PMMA infiltration. This was attributed to the properties of PMMA (density and mean atomic number) being very similar to those of the protein; therefore, the sample behaves like a two-phase system which allows the establishment of a monotonic relation between density and BSE coefficient. With the newly developed standards (brominated and iodinated dimethacrylate esters) for BSE microscopy of bone, grey levels can be converted to absolute BSE coefficients by linear interpolation, from which equivalent densities can be determined.

Bone Density↗
PubMed1997

The predictive value of tumor regression rates during chemoradiation therapy in patients with advanced head and neck squamous cell carcinoma.

OBJECTIVE: The value of tumor regression rates in predicting survival outcome during chemoradiation therapy was prospectively evaluated. METHODS AND MATERIALS: Sixty-two patients diagnosed with locally advanced stage III/IV unresectable head and neck squamous cell carcinoma underwent weekly clinical and endoscopic serial assessment of primary and nodal tumor sizes during chemoradiation therapy between July 1993 and September 1995. Chemoradiation therapy consisted of protocol treatment using supradose intra-arterial targeted cisplatin (SIT-P) at 150 mg/m2 four times at weekly intervals along with intravenous sodium thiosulfate at 9 g/m2 and concurrent conventionally fractionated radiotherapy at 1.8 to 2.0 Gy/fraction (fx) to a total dose of 68 to 74 Gy. Tumor reduction was serially measured as a percentage of the original pretreatment size at weekly intervals by the same team of surgical and radiation oncologists. Correlations were then made between tumor regression rates and survival. RESULTS: Complete or near complete regression of disease during chemoradiation therapy as compared with nonresponsive/partially responsive disease was associated with better survival outcome (P = 0.001 and P = 0.013, respectively). Among patients exhibiting complete or near complete regression of disease, rapid tumor reduction (median = 4.2 weeks) was associated with inferior survival outcome when compared with slower disease regression (median = 6.4 weeks, P = 0.007). CONCLUSIONS: Our findings fail to support the "traditional" hypothesis that rapid tumor regression during treatment is predictive of an improved survival outcome. Treatment strategies that alter ongoing therapy based upon initial tumor regression rates should be avoided.

Antidotes↗
PubMed1997

X-ray microtomography: 3-dimensional imaging of teeth for computer-assisted learning.

X-ray microtomography (XMT), a miniaturised form of computed tomography, has been used to generate 3-dimensional volume data sets of the X-ray absorption of human teeth in vitro, with a resolution of approximately 40 microns (cubic voxel sidelength). Examples are presented of images relevant to dental morphology, cariology, and cavity preparation and restoration. Applications of XMT imaging to dental education are discussed in the context of new approaches to visual learning through computer-assisted methods.

Computer-Assisted Instruction↗
PubMed1997

Inhibition of diabetes by an insulin-reactive CD4 T-cell clone in the nonobese diabetic mouse.

A cloned Th1 cell line was isolated from pancreatic lymph nodes of NOD mice that carries a T-cell receptor encoding Vbeta14 and proliferates in response to NOD islets, islet supernatant, and crystalline bovine and rat insulin, specifically to a B-chain peptide bound to IA(g7). The response to islet supernatant was reduced by 75% by anti-insulin antibody treatment. The insulin-reactive clone reduced insulitis and totally blocked the development of spontaneous diabetes in NOD mice (n = 8) as well as the adoptive transfer of diabetes into irradiated NOD mice following the injection of splenocytes from diabetic mice (n = 13). Trafficking of the adoptively transferred cells was assessed by labeling the clone or diabetic splenocytes with a fluorescent marker (DiI). The labeled clone was detected in the islet periphery, whereas labeled splenocytes alone invaded the islets by 3 days. In contrast, the protective clone dramatically delayed and reduced the number of labeled diabetic splenocytes infiltrating the islet, although their appearance in the spleen was unaffected. In vitro, the clone as well as supernatant derived from the clone blocked the proliferation of diabetic NOD splenocytes to islets. This inhibitory effect was diminished by anti-transforming growth factor-beta. In conclusion, an insulin-specific Th1 cell was isolated from NOD mice that traffics to the islet and prevents the spontaneous development and the adoptive transfer of diabetes. It appears to act locally by releasing transforming growth factor-beta and/or other factors that inhibit homing to and/or proliferation of diabetic splenocytes within the islet. These findings may provide insights into and suggest mechanisms for the protective effects of insulin therapy against diabetes.

Adoptive Transfer↗